Non-nucleoside reverse transcriptase inhibitors

ABSTRACT

A compound of the formula (Y): where; R 1  is O, S; R 2  is a nitrogen-containing heterocycle; R 3  is H, C 1 -C 3  alkyl; X is —(CR 8 R 8 ′) n -D-(CR 8 R 8 ′) m —; D is a bond, —NR 9 —, —O—, —S—, —S(═O)— or —S(═O) 2 —; n and m are independently 0, 1 or 2, R 8  and R 8 ′ are independently H, C 1 -C 3  alkyl, haloC 1 -C 3 alkyl, hydroxy, or R 8  and R 8 ′ together with their adjacent C atom is —C(═O)—; R 9  is independently H, C 1 -C 3  alkyl; E is CH 2 —, —CHOH—, —C(═O)—, —NR 9 —, —O—, —S—, —S(═O) 2 —; n and m are independently 0, 1 or 2; p and q are independently 0, 1 or 2, where p+q≦2; R 10  is an optionally substituted carbocycle or heterocycle; R 11  is independently H, C 1 -C 3  alkyl, halo substituted C 1 -C 3 alkyl, hydroxy; have utility as HIV antivirals.

This application is a national phase under 35 U.S.C § 371 of PCTInternational Application No. PCT/EP2003/009872 which has anInternational filing date of Sep. 5, 2003, which designated the UnitedStates of America.

TECHNICAL FIELD

This invention relates to non-nucleoside reverse transcriptaseinhibitors active against HIV-1 and having an improved resistance andpharmacokinetic profile. The invention further relates to novelintermediates in the synthesis of such-compounds and the use of thecompounds in antiviral methods and compositions.

BACKGROUND OF THE INVENTION

Our co-pending, but as of the priority date, unpublished PCTapplications nos PCT/EP02/02328 & PCT/EP02/02346 claim novel NNRTIs ofthe formula I/II

where:

-   R₁ is O, S;-   R₂ is an optionally substituted, nitrogen-containing heterocycle,    wherein the nitrogen is located at the 2 position relative to the    (thio)urea bond;-   R₂ is an optionally substituted, nitrogen-containing heterocycle,    wherein the nitrogen is located at the 2 position relative to the    (thio)urea bond;-   R₃ is H, C₁-C₃ alkyl,-   R₄-R₇ are independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, haloC₁-C₆ alkyl, C₁-C₆ alkanoyl, haloC₁-C₆ alkanoyl,    C₁-C₆ alkoxy, haloC₁-C₆ alkoxy, C₁-C₆ alkyloxyC₁-C₆ alkyl, haloC₁-C₆    alkyloxyC₁-C₆ alkyl, hydroxyC₁-C₆ alkyl, aminoC₁-C₈ alkyl,    carboxyC₁-C₆ alkyl, cyanoC₁-C₆ alkyl, amino, carboxy, carbamoyl,    cyano, halo, hydroxy, keto and the like;-   X is —(CH₂)_(n)-D-(CH₂)_(m)— or X is —(CRaRb)_(c)—-   D is —NR₈—, —O—, —S—, —S(═O) or —S(═O)₂—-   R₈ is H, C₁-C₃ alkyl-   R_(a) and R_(b) are independently H, C₁-C₃ alkyl, OH or R_(a) and    R_(b) together are ═O-   n and m are independently 0 or 1;-   c is 1, 2 or 3    and pharmaceutically acceptable salts and prodrugs thereof.

Although the urea and thiourea NNRTIs disclosed in the above documentsare exquisitely active against reverse transcriptase, especially that ofHIV-1, the nature of the HIV virus with its extreme lack of replicativefidelity and consequent tendency to rapid resistance development promptsa demand for further antiretroviral agents with enhanced antiviralperformance against problematic drug escape mutants, notably at the RT100, 103 and/or 181 positions.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with a first aspect of the invention there are providedcompounds of the formula Y:

where;

-   R₁ is O, S;-   R₂ is a nitrogen-containing heterocycle, wherein a nitrogen is    located at the 2 position relative to the (thio)urea bond;-   R₃ is H, C₁-C₃ alkyl,-   R₄-R₇ are independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, haloC₁-C₆ alkyl, C₁-C₆ alkanoyl, haloC₁-C₆ alkanoyl,    C₁-C₆ alkoxy, haloC₁-C₆ alkoxy, C₁-C₆ alkyloxyC₁-C₆ alkyl, haloC₁-C₆    alkyloxyC₁-C₆ alkyl, hydroxyC₁-C₆ alkyl, aminoC₁-C₆ alkyl,    carboxyC₁-C₆ alkyl, cyanoC₁-C₆ alkyl, amino, carboxy, carbamoyl,    cyano, halo, hydroxy, keto;-   X is —(CR₈R₈′)_(n)-D-(CR₈R₈′)_(m)—;-   D is a bond, —NR₉—, —O—, —S—, —S(═O)— or —S(═O)₂—;-   n and m are independently 0, 1 or 2, provided that they are not both    0 when D is a bond;-   R₈ and R₈′ are independently H, C₁-C₃ alkyl, haloC₁-C₃alkyl,    hydroxy, or R₈ and R₈′ together with their adjacent C atom is    —C(═O)—-   R₉ is independently H, C₁-C₃ alkyl;-   E is —CH₂—, —CHOH—, —C═O—, —NR₉—, —O—, —S—, —S(═O)₂—;-   p and q are independently 0, 1 or 2, where p+q 2;-   R₁₀ is an optionally substituted, saturated or unsaturated 5-7    membered carbocyclic ring or an optionally substituted, saturated or    unsaturated 5-7 membered heterocyclic ring containing 1 to 3 hetero    atoms selected from O, N and S;-   R₁₁ is independently H, C₁-C₃ alkyl, halo substituted C₁-C₃alkyl,    hydroxy;-   with the proviso that —(CHR₁₁)_(p)-E-(CHR₁₁)_(q)—R₁₀ is not    unsubstituted phenoxy;    and pharmaceutically acceptable salts and prodrugs therof.

The currently preferred value for R₁ is O, that is a urea derivative,although R₁ as S (ie a thiourea derivative) is also highly potent.

Representative values for R₂ include thiazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, indolyl, triazolyl,tetrazolyl, piperidyl, piperazinyl and fused rings such asbenzothiazolyl, benzopyridyl, benzodiazolyl, benzimidazolyl, quinolyl,purinyl and the like, any of which can be optionally substituted, inaddition to the —(CHR₉)_(p)-E-(CHR₉)_(q)—R₁₀ substituent, for examplewith C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₈ alkynyl, C₂-C₈alkenoxy, C₁-C₆ alkoxyC₁-C₆ alkyl, C₁-C₆ alkanoyl, haloC₁-C₆ alkyl,C₁-C₄ alkanoyloxy, C₁-C₄ alkylthio, amino (including C₁-C₃alkyl-substituted amino), carboxy, carbamoyl, cyano, halo, hydroxy,aminomethyl, carboxymethyl, hydroxymethyl, nitro, —SO₂Q or —C(═O)Q,where Q is C₁-C₆ alkyl, halosubstituted C₁-C₆ alkyl and the like.

Preferred R₂ values include pyrid-2-yl and thiazol-2-yl.

Heteroatoms in R₂ can be derivatised, such as with C₁-C₆ alkyl, oxo andthe like, but are preferably underivatised. The—(CHR₉)_(p)-E-(CHR₉)_(q)—R₁₀ substituent to R₂ may be ortho or metarelative to the bond to the (thio)urea function but is preferably para.

Conveniently, p and q are 0 and E represents a thioether, secondaryamine or especially an ether function. A further convenient—CHR₁₁-E-CHR₁₁— group is methylene, ethylene or propylene, optionallysubstituted with one to 3 halo or 1 hydroxy or keto groups. A stillfurther convenient configuration for —CHR₁₁-E-CHR₁₁— is oxymethyl oroxyethyl.

Representative R₁₀ groups include phenyl, cycloalkyl, cycloalkenyl,pyridyl, furyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, indolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl andmorpholino.

The optional substituents to R₁₀ include one to three substituentsincluding halo (such as fluoro), cyano, morpholinomethyl, morpholinoketoand the like.

Favoured R₁₀ groups include 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl,3,5-difluorophenyl, 2,3,4-triflourophenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 4-cyano-3-fluorophenyl, 3-cyano-5-fluorophenyl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-fluorpyrid-3-yl, piperazinyl,morpholinyl and piperidyl.

Convenient —(CHR₁₁)-E-(CHR₁₁)R₁₀ values thus include pyrid-3-yloxy,pyrid-4-yloxy, fluoro- or cyano-substituted pyrid-3-yloxy, fluoro- orcyano-substituted pyrid4-yloxy, 4-fluoro-3-N-morpholinornethylphenoxy,3-N-morpholinornethylphenoxy, 4-fluoro-3-N-morpholino-keto-phenoxy,4-fluorophenoxy, 3-fluorophenoxy, 3,4-difluorophenoxy, 4-cyanoph enoxy,3-cyanophenoxy, 4-cyano-3-fluorophenoxy, 3-cyano-4-fluorophenoxy,3-cyano-5-fluorophenoxy and the like.

The currently preferred value for R₃ is H.

Preferably R₄ is hydrogen, halo or hydroxy, especially fluoro.

Preferably R₅ is halo, C₁₋₃ alkylcarbonyl, C₁₋₃alkyloxy or H, especiallyfluoro and most preferably H.

Preferably R₆ is hydrogen, halo, C₁-C₃alkyloxy, C₁-₃alkylcarbonyl, cyanoor ethynyl, especially methoxy or fluoro and most preferably H.

Preferably R₇ is hydrogen, halo, C₁₋₃alkyloxy, or C₁₋₃alkylcarbonyl,most preferably fluoro.

Preferably R₅ and R₆ are H and R₄ and R₇ are halo, most preferably bothare fluoro.

The compounds of formula I may be administered as a racemic mixture, butpreferably the cyclopropyl moiety intermediate the (thio)urea function,X and the phenyl ring (denoted Y below) is at least 75% such as around90% enantiomerically pure with respect to the conformation:

Prefered optical isomers of the compounds of formula I show a negativeoptical rotation value. Such isomers, for example when X is —O—CH₂—,tend to elute less rapidly from a chiral chromatagram, for examplechiral AGP 150×10 mm, 5 μm; Crom Tech LTD Colomn, flow rate 4 ml/min,mobile phase 89 vol % 10 mM HbAc/NH₄OAc in acetonitrile. On the basis ofpreliminary x-ray crystallography analysis a presently favoured absoluteconfiguration appears to be:

The currently preferred value for D is —O—. Convenient values for n andm include 1:0 and 1:1. Preferred values of n:m include 0:2 andespecially 0:1, that is a chroman derivative. Conveniently each R8 andR8′ is H. Alternatively, in the case where n is 0 and m is 1, R8 isadvantageously H and R8′ is OH.

Particularly preferred compounds have stereochemistry corresponding to(1S,1aR,7bR)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl. For thesake of clarity, it is noted that the structure:

The expression C₁-C_(n) alkyl, where n is 3, 6, 7 etc or lower alkylincludes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, t-butyl, n-pentyl, n-hexyl, 3-methyl pentyl and the like. Theterm halo refers to chloro, bromo, fluoro and iodo, especially fluoro.C₁-C_(n) alkoxy refers to groups such as methoxy, ethoxy, propoxy,t-butoxy and the line. C₂-C_(n) alkenyl refers to groups such as vinyl,1-propen-2-yl, 1-buten-4-yl, 1-penten-5-yl, 1-buten-1-yl and the like.C₁-C_(n) alkylthio includes methylthio, ethylthio, t-butylthio and thelike. C₁-C_(n) alkanoyloxy includes acetoxy, propionoxy, formyloxy,butyryloxy and the like. C₂-C_(n) alkenoxy includes ethenyloxy,propenyloxy, iso-butoxyethenyl and the like. HaloC₁-C_(n) alkyl(including complex substituents comprising this moiety such ashaloC₁-C_(n) alkyloxy) includes alkyls as defined herein substituted 1to 3 times by a halogen including trifluoromethyl, 2-dichloroethyl,3,3-difluoropropyl and the like. The term amine includes groups such asNH₂, NHMe, N(Me)₂ which may optionally be substituted with halogen,C₁-C₇ acyloxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, nitro, carboxy, carbamoyl,carbamoyloxy, cyano, methylsulphonylamino and the like. Carboxy,carboxymethyl and carbamoyl include the corresponding pharmaceuticallyacceptable C₁-C₆ alkyl and aryl esters.

Prodrugs of the compounds of formula I are those compounds whichfollowing administration to a patient release a compound of the formulaI in vivo. Typical prodrugs are pharmaceutically acceptable ethers andespecially esters (including phosphate esters) when any of R₄-R₇represent an hydroxy function, pharmaceutically acceptable amides orcarbamates when any of the R₂ substituent or R₄-R₇ represent an aminefunction or pharmaceutically acceptable esters when the R₂ substituentor R₄-R₇ represent a carboxy function. Pharmaceutically acceptableesters include alkyl esters, including aceylm, ethanoyl, butyryl,t-butyryl, and pivaloyl, phosphate esters and sulphonic esters (ie thosederived from RSO₂OH, where R is lower alkyl or aryl). harmaceuticallyacceptable esters include lower alkyl ethers and the ethers disclosed inWO00/47561, especially methoxyaminoacyl and ethoxyaminoacyl.

The compounds of formula I can form salts which form an additionalaspect of the invention. Appropriate pharmaceutically acceptable saltsof the compounds of formula I include salts of organic acids, especiallycarboxylic acids, including but not limited to acetate,trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate,malate, pantothenate, isethionate, adipate, alginate, aspartate,benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate,glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate,palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate,tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate,organic sulphonic acids such as methanesulphonate, ethanesulphonate,2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate,benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate;and inorganic acids such as hydrochioride. hydrobromide, hydroiodide,sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoricand sulphonic acids.

Hydroxy protecting group as used herein refers to a substituent whichprotects hydroxyl groups against undesirable reactions during syntheticprocedures such as those O-protecting groups disclosed in Greene,“Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York(1981)). Hydroxy protecting groups comprise substituted methyl ethers,for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, t-butyl and other lower alkyl ethers,such as isopropyl, ethyl and especially methyl, benzyl andtriphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, forexample, 2,2,2-trichloroethyl; silyl ethers, for example,trimethylsilyl, t-butyidimethylsilyl and t-butyidiphenylsilyl; andesters prepared by reacting the hydroxyl group with a carboxylic acid,for example, acetate, propionate, benzoate and the like.

Similarly, N-protecting group as used herein refers to thoseconventional N-protecting groups disclosed in Greene, “Protective Groupsin Organic Synthesis”, John Wiley & Sons New York 1981.

The invention further provides pharmaceutical compositions comprisingthe compounds of the invention and pharmaceutically acceptable carriersor diluents therefor. Additional aspects of the invention providemethods for the inhibition of HIV comprising administering a compound ofthe formula I to a subject afflicted with or exposed to HIV-1. The HIV-1may comprise a drug escape mutant, such as HIV strain comprising themutations at the 100, 103 and/or 181 mutations, especially K103N.

The invention also extends to the use of the compounds of formula I intherapy, such as in the preparation of a medicament for the treatment ofHIV infections.

In treating conditions caused by HIV, the compounds of formula I arepreferably administered in an amount to achieve a plasma level of around100 to 5000 nM, such as 300 to 2000 nM. This corresponds to a dosagerate, depending on the bioavailability of the formulation, of the order0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A typical dosagerate for a normal adult will be around 0.05 to 5 g per day, preferably0.1 to 2 g such as 500-750 mg, in one to four dosage units per day. Aswith all pharmaceuticals, dosage rates will vary with the size andmetabolic condition of the patient as well as the severity of theinfection and may need to be adjusted or concomitant medications.

In keeping with the usual practice with HIV inhibitors it isadvantageous to co-administer one to three additional antivirals toprovide synergistic responses and to ensure complementary resistancepatterns. Such additional antivirals may include AZT, ddI, ddC, D4T,3TC, DAPD, alovudine, abacavir, adefovir, adefovir dipivoxil,bis-POC-PMPA, GW420 867X, foscamet, hydroxyurea, Hoechst-Bayer HBY 097,efavirenz, trovirdine, capravirine, nevirapine, delaviridihe,tipranavir, emtricitabine, PFA, H2G (omaciclovir), MIV-606(valomaciolovir stearate), TMC-126, TMC-125, TMC-120, efavirenz,DMP-450, loviride, ritonavir, (including kaletra), lopinavir,saquinavir, lasinavir, indinavir, amprenavir, amprenavir phosphate,nelfinavir and the like, typically at molar ratios reflecting theirrespective activities and bioavailabilities. Generally such ratio willbe of the order of 25:1 to 1:25, relative to the compound of formula I,but may be lower, for instance in the case of cytochrome antagonistssuch as ritonavir.

Compounds of the invention are typically prepared as follows:

Compounds of the general formula (I), wherein R₁ is O (urea) or S(thiourea), R₂ is, for instance, a 5-substituted pyrid-2-yl (Re is the(CHR₁₁)_(p)-E-(CHR₁₁)_(q)—R₁₀ moiety), and R₃ is H, are prepared bymethods shown in Scheme 1. The cyclopropanecarboxylic acid 1-Scheme-1 isconverted to the acyl azide and heated to 120° C. to induce Curtiusrearrangement and provide the isocyanate 2-Scheme-1. The urea 3-Scheme-1is obtained by-coupling of the isocyanate with the relevantlysubstituted 2-aminopyridine. Hydrolysis of the isocyanate as in step (c)which results in the cyclopropylamine 4-Scheme-1, followed by reactionwith a 2-pyridyl isothiocyanate provides the thiourea 5-Scheme-1. Theisothiocyanate may be prepared from the optionally ring substituted2-aminopyridine by known methods, such as treatment with thiophosgene orthiocarbonyidiimidazole. R₃ variants of formula I are preparedcorrespondingly using the appropriately amine-substituted amino-R₂, ie2-(N-methylamino)pyridine for R₃ as methyl. Many 2-aminopyridines arecommercially available and others are described in literature, forexample those shown in Scheme 2. R₁═S compounds can alternatively beprepared from the isothiocyanate corresponding to 2-Scheme 2 or fromamine 3-Scheme 2 and amino-R₂ in conjunction with an RC(═S)R′ both asdescribed in WO 9303022. Although Scheme 1 has been illustrated with asubstituted pyridyl it is readily apparent that corresponding couplingscan be used for other R₂ variants such as(—CHR₁₁)_(p)-E-(CHR₁₁)_(q)—R₁₀)-substituted thiazolyl, pyrazinyl,benzothiazolyl, pyrimidinyl etc.

Replacement of the bromine in 5-bromo-2-nitropyridine by a (substituted)phenoxy group, followed by reduction of the nitro group affords thesubstituted 2-amino-5-phenoxypyridine. Compounds with a thioetherlinkage can be prepared analogously. The methodology developed byBuchwald can be used for the syhtesis of nitrogen containing5-substituents including heterocyclic rings. A general description ofthis reaction is shown in Scheme 2. A protected iodopyridine derivativeis reacted with an appropriate amine in a Pd catalysed reaction to givean intermediate that is deprotected to give the appropriate5-aminosubstituted pyridines.

Compounds of the general formula (I), wherein R1 is O (urea) or S(thiourea), R2 is, for example, a 5-substituted pyrid-2-yl, R3 is H, Xis -D-CH₂, and wherein the cyclopropyl moiety has the relativeconfiguration

are prepared by methods shown in Scheme 3. Cyclopropanation of thedouble bond in the chromene 1-Scheme-3 with ethyl diazoacetate iscatalyzed by cuprous or rhodium(II) salts such as CuI, (CuOTf)₂-benzene,and Rh₂(OAc)₄ in solvents such as dichloromethane, 1,2-dichloroethane,or chloroform. The reaction provides a diastereomeric mixture of thecyclopropanecarboxylic acid ethyl esters 2-Scheme-3, with the all cisrelative configuration, and its trans isomer 3-Scheme-3. Separation bycolumn chromatography of the cis and trans diastereomers may beaccomplished at this stage, followed by hydrolysis of the isolated2-Scheme-3, such as by refluxing in aqueous methanolic LiOH, to yield aracemic mixture of the all cis cyclopropanecarboxylic acid 4-Scheme-3,as described in step (b). Alternatively, the diastereomeric mixture ofethyl esters may be subjected to hydrolysis, and separation conducted onthe mixture of cyclopropanecarboxylic acids to provide the isolated allcis isomer, as in step (c). Step (d) involves isolation of the cis ethylester 2-Scheme-3 which may also be done by selective hydrolysis of thetrans 3-Scheme-3 at lower temperatures, such as treatment with aqueousmethanolic NaOH at ambient temperature. The isolated cis ethyl ester maythen be hydrolyzed in the usual manner to the cyclopropanecarboxylicacid 4-Scheme-3. The cyclopropanecarboxylic acid is subjected to themethods outlined in Scheme 1 to obtain the urea or thiourea 5-Scheme-3.The chromenes 1-Scheme-3 are prepared by methods shown in Schemes 4, 5,and 6.

Although this scheme 3 has been illustrated with a D=O variant it willbe apparent that corresponding manipulations will be available to theD=S, S═O; S(═O)₂ and D=NR₈ variants. When R₈ is H, the nitrogen istypically protected with a conventional secondary amine protectinggroup, such as those described in Greene & Wuts Protective Groups inOrganic Synthesis 2^(nd) ed, Wiley NY 1991).

Scheme 4 describes the preparation of chromenes, including many fromcommercially available disubstituted phenols, such as those wherein thesubstitution pattern in the benzene ring is as follows: R4 and R7 arehalo; R4 and R6 are halo; R5 and R7 are halo; R4 is halo and R7 is C₁₋₃alkylcarbonyl; and R4 is hydroxy while R5 is C₁₋₃ alkylcarbonyl.Reaction of the available disubstituted phenol 1-Scheme-4 with3-bromopropyne in the presence of a base, such as K₂CO₃ in acetone orNaH in DMF, results in nucleophilic substitution of the halide toprovide the ether 2-Scheme-4. Ring closure may be accomplished byheating the ether in N,N-dimethylaniline or polyethylene glycol to yieldthe chromene 3-Scheme-4.

Scheme 5 describes the preparation of chromenes used as startingmaterial in Scheme 3, from the appropriately substituted chromanones,which are readily accessed from commercially available chromanones, forexample those wherein one of the positions in R₄ to R₇ is substitutedwith halo or C₁₋₃ alkoxy. Conversion of the carbonyl group in4-chromanone 1a-Scheme-5 and to the correponding alcohol by a suitablereducing agent such sodium borohydride in ethanol provides 2-Scheme-5.Refluxing the alcohol with small amounts of acid, such as p-TsOH intoluene, causes dehydration of 2-Scheme-5 to the desired chromene1-Scheme-3. Corresponding manipulations will be available for other Dvariants. For example the corresponding 2H-1-benzothiopyran is readilyprepared from commercially available (substituted) thiochroman-4-ones byreaction with a reductant such as a metal hydride for example lithiumaluminium hydride in an organic solvent such as ether, followed bydehydration such as refluxing with an acid for example potassium acidsulphate or the like.

Chromenes, for use as starting material in Scheme 3, are prepared fromsubstituted o-hydroxybenzaldehydes as shown by methods outlined inScheme 6. Reaction of 1-Scheme-6 with allyl bromide in the presence of abase such as K₂CO₃ in acetone, results in nucleophilic substitution ofthe halide to provide the ether 2-Scheme-6. Witting reaction transformsthe aldehydic group into the olefin and provides 3-Scheme-6. The pair ofterminal double bonds may undergo metathesis intramolecularly bytreatment with a catalyst such as the ruthenium complex Grubb's catalystin step (c) to produce the chromene. Alternatively 1-Scheme-6 can becyclised directly as shown in step d) in the legend above.

Chromenes, for use as starting material in Scheme 3, are prepared fromsubstituted o-hydroxybenzaldehydes as shown by methods outlined inScheme 6. Reaction of 1-Scheme-6 with allyl bromide in the presence of abase, such as K₂CO₃ in acetone, results in nucleophilic substitution ofthe halide to provide the ether 2-Scheme-6. Witting reaction transformsthe aldehydic group into the olefin and provides 3-Scheme-6. The pair ofterminal double bonds may undergo metathesis intramolecularly bytreatment with a catalyst such as the ruthenium complex Grubb's catalystin step (c) to produce the chromene. Alternatively 1-Scheme-6 can becyclised directly as shown in step d) in the legend above.

Pd(0) catalyzed coupling of the triflate 1-Scheme-7 leads to thereplacement of the trifluoromethanesulfonyloxy group and theintroduction of other substitutents at R₆. Thus, Scheme 7 provides thepreparation of synthesis intermediates for use in scheme 3 to give theurea or thiourea 5-Scheme-3 wherein R₆ is cyano, ethynyl, or C₁₋₃alkylcarbonyl.

Convenient routes to compounds wherein X is —CH₂—O— are depicted inScheme 8, where R^(a) and R^(b) are optional substituents R₄-R₇, whichare suitably protected with conventional protecting groups as necessaryand R^(c) is a lower alkyl ester. Optionally substituted phenol1-Scheme-8 which is hydroxy-protected with a protecting group such asmethyl, MOM and the like is reacted with a base such as BuLi or the likein a solvent such as THF or the like and transformed to zinc salt byadding-zinc chloride or the like. A catalyst such as Pd(OAc)₂ or thelike is added along with an activated acrvlate such as loweralkyl-cis-3-haloacrylate, for example BrCH═CHCOOEt or the like. Thereaction mixture is cooled and a reducing agent such as DIBAL or thelike is added portionwise and quenched to yield 2-Scheme-8. A hydrazonesuch as the p-toluenesulfonylhydrazone of glyoxylic acid chloride or thelike and a base such as N,N-dimethylaniline or the like is added in asolvent such as CH₂Cl₂ or the like followed by the addition of anotherbase such as Et₃N or the like to yield 3-Scheme-8. The reaction productis dissolved in a solvent-such as dichloromethane or the like which ispreferably degassed. A chiral Doyle's catalyst such as Rh₂(5-R-MEPy)₄(U.S. Pat. No. 5,175,311, available from Aldrich or Johnson Matthey), orthe like is added to yield 4-Scheme-8 in a high enantiomeric excess suchas greater than 80, preferably greater than 90% ee. Preferably, thiscompound is first reacted with BBr₃ in dichloromethane followed by theaddition of acetonitrile the reaction mixture and finallysodiumhydroxide is added to give 6-Scheme-8. Alternatively, this product(4-Scheme-8) is ring-opened with an electrophile preferably HBr or thelike under in conjunction with an acid such as AcOH or the like. Underacid conditions a spontaneous ring closure takes place to formchromenone 5-Scheme-8. When subjected to basic conditions such as NaOHor the like, the chromenone rearranges to form thechromencyclopropylcarboxylic acid 6-Scheme-8. Alternatively, 4-Scheme-8,for instance when the phenolic protecting group is MOM, can be subjectedto basic conditions such as NaOH, carbon dioxide and a lower alkylhalide such as iPrl in a solvent such as DMSO to open the lactone andyield the alkyl ester 7-Scheme-8. Displacement of the hydroxy protectinggroup and ring closure with the free hydroxymethyl moiety occurs inacidic conditions such as iPrOH/HCl or the like followed by DEAD; PPH₃in an organic solvent such as THF or the like. Alternatively, in aconvergent approach, compound 1-Scheme-8 is reacted with BuLi andtransformed to a zinc salt. This salt reacted with thecyclopropyliodide, 9-Scheme-8, in a palladium-catalyzed reaction to giveafter reaction with Jone's reagent compound 4-Scheme-8. This carboxylicacid is in turn converted to the isocyanate as shown in Scheme 1 andsubsequently to the heteroarylurea or heteroaryithiourea of the FormulaI.

EINBETTEN

R₃ variants of formula I are prepared correspondingly using theappropriately amine-substituted amino-R₂, is5-substitued-2-(N-methylamino)pyridihe derivatives for R₃ as methyl.Although Scheme 1 has been iilustrated with a substituted pyrdyi it isreadily apparent that corresponding couplings can be used for other R₂variants such as substituted thiazolyl, pyrazinyl, benzothiazolyl,pyrimidinyl, etc.

EINBETTENEINEBETTENEINBETTEN

Compounds wherein X is an optionally substituted alkylene areconveniently prepared by scheme 9:

Scheme 9 describes the preparation of tetralins, indanes and homologues,used as starting material in the schemes above from knownmonosubstituted tetralones etc, wherein positions R₄ to R₇ is/aresubstituted, for example with halo or C₁₋₃ alkoxy. Conversion of thecarbonyl group in 1-tetralone 1b-Scheme-9 to the corresponding alcoholby a suitable reducing agent such sodium borohydride in ethanol provides2-Scheme-9. Refluxing the alcohol with small amounts of acid, such asp-TsOH in toluene, causes dehydration of 2-Scheme-9 to the desiredtetralin 1-Scheme-9. Corrresponding reactions are applicable to n=1 or3.

Favoured compounds of formula I include

-   (−)-cis-1-(5-(pyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoropyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-cyano-pyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-fluoropyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cycopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-cyano-pyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(5-fluoro-pyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(5-cyano-pyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cryclopopa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(pyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoropyrid-3-yloxy)-pyridin-2-yl3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-cyanopyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-fluoropyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-cyanopyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)urea.-   (−)-cis-1-(5-(5-fluoropyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(5-cyanopyrid-3-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(pyridin-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-fluoropyrid-4-yloxy)pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-cyano-pyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromnene-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoropyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-cyanopyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(pyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-fluoropyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-cyanopyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoropyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cryclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-cyanopyrid-4-yloxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea.-   (−)-cis-1-(5-(2-fluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-fluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-fluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2,4-fluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2,3-difluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2,5-difluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene1-yl)-urea,-   (−)-cis-1-(5-(2,6-difluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3,5-difluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3,4-difluorophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoro-3-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-fluoro-2-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-fluoro-4-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-fluoro-3-cyanophenoxy)-pyridin-2-yl)-3-(4,7-diflubro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(3-fluoro-5-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(5-fluoro-3-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(4-fluoro-2-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1.1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoro-4-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(5-fluoro-2-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoro-5-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   (−)-cis-1-(5-(6-fluoro-2-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   (−)-cis-1-(5-(2-fluoro-6-cyanophenoxy)-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,    and the corresponding thioureas of each of these compounds;    and pharmaceutically acceptable salts thereof, especially    enantiomerically enriched, for example greater than 80% by weight,    preferably >90%, such as >97% ee or pure preparations comprising the    (−) enantiomer.

While it is possible for the active agent to be administered alone, itis preferable to present it as part of a pharmaceutical formulation.Such a formulation will comprise the above defined active agent togetherwith one or more acceptable carriers or excipients and optionally othertherapeutic ingredients. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient.

The formualtions include those suitable for rectal nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal)administration, but preferably the formulation is an orally administeredformulation. The formulations may conveniently be presented in unitdosage form, e.g. tablets and sustained release capsules, and may beprepared by any methods well known in the art of pharmacy.

Such methods include the step of bringing into association the abovedefined active agent with the carrier. In general, the formulations areprepared by uniformly and intimately bringing into association theactive agent with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. The invention extendsto methods for preparing a pharmaceutical composition comprisingbringing a compound of Formula I or its pharmaceutically acceptable saltin conjunction or association with a pharmaceutically acceptable carrieror vehicle. If the manufacture of pharmaceutical formulations involvesintimate mixing of pharmaceutical excipients and the active ingredientin salt form, then it is often preferred to use excipients which arenon-basic in nature, i.e. either acidic or neutral.

DETAILED DESCRIPTION

Various aspects of the invention will now be illustrated by way ofexample only with reference to the following non-limiting examples.

EXAMPLE 1

5-(3-flurophenoxy)-2-nitropyridine

Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) wasmixed with 3-5 ml of dry dimethylformamide and 3-fluorophenol (0.244 ml,2.7 mmol) was added to the stirred suspension. When the gas evolutionwas ceased the reaction mixture was heated at stirring at 60° C. and5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reactionmixture in one portion. The reaction-mixture was stirred at 60° C. forabout 12 hours. The reaction mixture was then mixed with 50 ml of waterand extracted into methylene chloride (3×20 ml). Organic extract waswashed with water and brine, dried over magnesium sulfate andconcentrated by rotary evaporation. The resulting mixture was purifiedby column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 190mg (33% yield) of desired product.

¹H-NMR (CDCl₃): 8.31 (d, 1H), 8.24 (d, 1H), 7.38 (dd, 1H), 7.08-7.20 (m,4H).

EXAMPLE 2

5-(3-fluorophenoxy)-2-pyridinamine

5-(3-fluorophenoxy)-2-nitropyridine was mixed with 15-20 ml of ethanoland bubbled with argon. About 20 mg of Pd/C was added to the reactionmixture and hydrogen gas was applied at normal pressure and ambienttemperature for 3-12 h. The reaction was monitored by TLC. After thereaction was complete, the reaction mixture was bubbled with argon,filtered through Celite and the solution obtained was concentrated byrotary evaporation to give 165 mg of desired aminopyridine (quantitativeyield).

¹H-NMR (CDCl₃): 7.92 (d, ˜1H), 7.22 (m, 2H), 6.73 (m, 2H), 6.62 (d tr,1H), 6.54 (d, 1H), 6.82 (dd, 2H), 6.64 (d, 1H), 4.42 (br s, 2H).

EXAMPLE 3

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-fluorophenoxy)-2-pyridinyl]urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ˜95% ee) was mixed with toluene (1,5 ml),triethylamine (1.1 eq), 5-(3-fluorophenoxy)-2-aminopyridine (1.1 eq),DPPA (1.1 eq) and bubbled with argon for about 5 min. The reactionmixture was then heated at stirring at 110° C. for 3 h under in a closedvial. The reaction mixture was concentrated by mtary evaporation andpurified by column chromatography on silica (30 g, ethylacetate/hexane1:1). Desired product was obtained as beige-white powder (60 mg, yield64%).

¹H-NMR (CDCl₃): 9.57 (br s, 1H), 9.47 (br s, 1H), 7.61 (d, 1H), 7.28 (m,2H), 6.89 (d, 1H), 6.79 (m, 2H), 6.70 (dd, 1H), 6.64 (d tr, 1H), 6.56(tr d, 1H), 4.45 (dd, 1H), 4.33 (dd, 1H), 3.80 (q, 1H), 2.59 (br tr,1H), 1.92-1.99 (m, 1H). LC-MS: M⁺428, M⁻4.26.

EXAMPLE 4

5-(4-fluorophenoxy)-2-nitropyridine

5-(4-Fluorophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 4-fluorophenol (0.3 g, 2.7 mmol) to give 310 mg ofproduct (54% yield).

¹H-NMR (CDCl₃): 8.31 (d, ˜1H), 8.24 (d, 1H), 7.39 (dd, 1H), 7.08-7.22(m, 4H).

EXAMPLE 5

5-(4-fluorophenoxy)-2-pyridinamine

5-(4-Fluorophenoxy)-2-pyridinamine was synthesized analogously toExample 2 from 5-(4-fluorophenoxy)-2-nitropyridine to give 270 mg ofproduct as beige powder.

¹H-NMR (CDCl₃): 7.88 (d, 1H), 7.17 (dd, 2H), 6.99 (m, 2H), 6.89 (m, 2H),6.52 (d, 1H), 4.42 (br s, 2H).

EXAMPLE 6

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-fluorophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]N′-[5-(4-fluorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(4-fluorophenoxy)-2-pyridinamine (50 mg, 0.24 mmol) to give 20 mg ofpure product as white powder (21% yield).

¹H-NMR (CDCl₃): 9.40 (br s, 1H), 9.05 (br s, 1H), 7.52 (d, 1H), 7.23(dd, 1H),7.00-7.08 (m, 2H), 6.86-6.94 (m, 2H), 6.73-6.82 (m, 2H), 6.56(d tr, 1H), 6.56 (tr d, 1H), 4.44 (dd, 1H), 4.33 (dd, 1H), 3.78 (q, 1H),2.59 (br tr, 1H), 1.92-1.99 (m, 1H). LC-MS: M⁺428, M⁻426.

EXAMPLE 7

5-(3-chlorophenoxy)-2-nitropyridine

5-(3-Chlorophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 3-chlorophenol (0.35 g, 2.7 mmol) to give 280 mg ofproduct (45% yield).

¹H-NMR (CDCl₃): 8.36 (d, 1H), 8.27 (d, 1H), 7.46 (dd, 1H), 7.40 (app dd,1H), 7.29 (ddd, 1H), 7.02 (ddd, 1H), 7.14 (app dd, 1H).

EXAMPLE 8

5-(3-chlorophenoxy)-2-pyridinamine

5-(3-Chlorophenoxy)-2-pyridinamine was synthesized analogously toExample 2 from 5-(3-chlorophenoxy)-2-nitropyridine to give 80 mg ofwhite powder after purification by column chromatography on silica (30g, EtOAc). Yield 32%.

¹H-NMR (CDCl₃): 7.90 (app dd, 1H), 7.25-7.31 (m, 1H), 7.15-7.22 (m, 2H),6.98-7.05 (m, 1H), 6.89-6.95 (m, 1H), 6.50 (dd, 1H), 4.42 (br s, 2H).

EXAMPLE 9

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-chlorophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-chlorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(3-chlorophenoxy)-2-pyridinamine (54 mg, 0.24 mmol) to give 28 mg ofpure product as white powder (28% yield).

¹H-NMR (CDCl₃): 9.46 (br s, 1H), 9.34 (br s, 1H), 7.59 (d, 1H),7.23-7.29 (m, ˜2H), 7.09 (m, 1H), 6.91 (m, 1H), 6.86 (d, 1H), 6.75-6.84(m, 2H), 6.56 (d tr, 1H), 4.46 (dd, 1H). 4.33 (dd, 1H), 3.80 (app. q,1H), 2.59 (br tr, 1H), 1.96 (m, 1H). LC-MS: M⁺410, M⁻408.

EXAMPLE 10

3-[(6-nitro-3-pyridinyl)oxy]benzonitrile

5-(3-Cyanophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 3-hydroxybenzonitrile (0.32 g, 2.7 mmol) to give solidmaterial after the reaction mixture was mixed with water, which wascollected by filtration and washed with ether to give 188 mg of yellowcrystals (32% yield).

¹H-NMR (CDCl₃): 8.39 (d, 1H), 8.30 (d, 1H), 7.60 (app. dd, 2H), 7.50(dd, 1H), 7.42 (m, 1H), 7.35-7.40 (m, 1H).

EXAMPLE 11

3-[(6-amino-3-pyridinyl)oxy]benzonitrile

3-[(6-amino-3-pyridinyl)oxy]benzonitrile was synthesized analogously toExample 2 from 3-[(6-nitro-3-pyridinyl)oxy]benzonitrile to give 31 mg ofbeige powder after purification by column chromatography on silica (30g, EtOAc). Yield 19%.

¹H-NMR (CDCl₃): 7.90 (d, 1H), 7.36-7.41 (m, 1H), 7.32 (d tr, 1H),7.14-7.22 (m, ˜3H), 6.56 (d, 1H), 4.65 (br s, 2H).

EXAMPLE 12

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-cyanophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-chlorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from3-[(6-amino-3-pyridinyl)oxy]benzonitrile (33 mg, 0.15 mmol). Solidmaterial formed in the reaction mixture was collected by filtration andwashed With ethanol to give 15 mg of pure product as slightly beigepowder (25% yield).

¹H-NMR (CDCl₃): 9.35 (br s, 1H), 7.65 (br s, 1H), 7.61 (d, 1H),7.38-7.48 (m, 2H), 7.27 (dd, 1H), 7.16-7.20 (m 2H), 6.78-6.86 (m, 1H),6.71 (d, 1H), 6.59 (d tr, 1H), 4.48 (dd, 1H), 4.33 (dd, 1H), 3.82 (q,1H), 2.62 (br tr, 1H), 1.98 (m, 1H). LC-MS: M⁺435, M⁻433.

EXAMPLE 13

4-[(6-nitro-3-pyridinyl)oxy]benzonitrile

5-(3-Cyanophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 3-hydroxybenzonitrile (0.7 g, 2.7 mmol) to give 555 mg ofproduct (46% yield).

¹H-NMR (CDCl₃): 8.40 (d, 1H), 8.32 (d, 1H), 7.77 (d, 2H), 7.56 (dd, 1H),7.20 (app d, 2H). Lc-MS: M⁻300 (+CH₃COO⁻).

EXAMPLE 14

4-[(6-amino-3-pyridinyl)oxy]benzonitrile

5-(3-Chlorophenoxy)-2-pyridinamine was synthesized analogously toExample 2 from 4-[(6-nitro-3-pyridinyl)oxy]benzonitrile (40 mg) to give31 mg of brown oil.

¹H-NMR (CDCl₃): 7.92 (d, 1H), 7.58 (app d, 2H), 7.21 (dd, 1H), 6.97 (appd, 2H), 6.58 (d, 1H), 4.56 (br s, 2H).

EXAMPLE 16

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-cyanophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-chlorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from3-[(6-amino-3-pyridinyl)oxy]benzonitrile (54 mg, 0.24 mmol) to give 18mg (yield 31%) of product as white powder after additional purificationby preparative HPLC (XTerra MS C18 19×100 mm column, water/acetonitrilewith 0.05% trifluoroacetic acid).

¹H-NMR (CDCl₃): 9.41 (br s, 1H), 9.30 (br s, 1H), 7.66 (d, 1H), 7.63(app d, 2H), 7.30 (dd, 1H), 6.96 (app d, 2H), 6.89 (d, 1H), 6.75-6.83(m, 1H), 6.57 (tr d, 1H), 4.48 (dd, 1H), 4.32 (dd, 1H), 3.81 (q, 1H),2.62 (br tr, 1H), 1.98 (m, 1H).

EXAMPLE 17

5-(2-fluorophenoxy)-2-nitropnridine

5-(4-Fluorophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 4-fluorophenol (0.3 g, 2.7 mmol) to give 326 mg ofproduct (57% yield).

¹H-NMR (CDCl₃): 8.34 (d, 1H), 8.25 (d, 1H), 7.38 (ddd, 1H), 7.22-7.34(m, 4H).

EXAMPLE 17A

5-(2-fluorophenoxy)-2-pyridinamine

5-(4-Fluorophenoxy)-2-pyridinamine was synthesized analogously toExample 2 from 5-(4-fluorophenoxy)-2-nitropyridine (326 mg) to give 200mg (70% yield) of product as white crystals after purification by columnchromatography on silica (25 g, EtOAc/hexane 1:1).

¹H-NMR (CDCl₃): 7.90 (d, 1H), 7.10-7.20 (m, 2H), 7.00-7.06 (m, 2H),6.88-6.95 (m, 1H), 6.50 (d, 1H), 4.55 (br s, ˜2H).

EXAMPLE 18

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2-fluorophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-flurophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(4-fluorophenoxy)-2-pyridinamine (50 mg, 0.24 mmol) to give 60 mg ofpure product as white powder (64% yield).

¹H-NMR (CDCl₃): 9.40 (br s, ˜1H), 9.39 (br s, ˜1H), 7.53 (d, 1H),7.07-7.26 (m, 4H), 6.93-7.00 (m, 1H), 6.84 (d, 1H), 6.74 (app d tr, 1H),6.53 (tr d, 1H), 4.43 (dd, 1H), 4.33 (dd, 1H), 3.78 (app q, 1H), 2.57(br tr, 1H), 1.90-1.97 (m, 1H). LC-MS: M⁺428, M⁻426.

EXAMPLE 19

5-(2,5-diflurophenoxy)-2-nitropyridine

5-(4-Fluorophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 2,5-difluorophenol (0.35 g, 2.7 mmol) to give 400 mg ofproduct (64% yield).

¹H-NMR (CDCl₃): 8.35 (brd, 1H), 8.28 (d, 1H), 7.44 (dd, 1H), 7.24-7.28(m, 1H), 6.96-7.06 (m, 2H).

EXAMPLE 20

5-(2,5-difluorophenoxy)-2-pyridinamine

5-(4-Fluorophenoxy)-2-pyridinamine was synthesized anaiogousiy toExample 2 from 5-(2,5-difluorophenoxy)-2-nitropyridine to give 370 mg ofproduct as beige powder.

¹H-NMR (CDCl₃): 7.92 (d, 1H), 7.21 (dd, 1H), 7.06-7.14 (m, 1H),6.67-6.74 (m, 1H), 6.56-6.52 (m, 1H), 6.53 (d, 1H), 4.44 (br s, 2H).

EXAMPLE 21

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2,5-difluorophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2,5-difluorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(2,5-difluorophenoxy)-2-pyndinamine (55 mg, 0.24 mmol) to give 40 mgof pure product as white powder (41% yield).

¹H-NMR (CDCl₃): 9.50 (br s, 1H), 9.45 (br s, 1H), 7.61 (d, 1H), 7.28(dd, ˜1H), 7.10-7.18 m, 1H), 6.86 (d, 1H), 6.75-6.84 (m, 2H), 6.61-6.66(m, 1H), 6.56 (tr d, 1H), 4.46 (dd, 1H), 4.32 (dd, 1H), 3.82 (q, 1H),2.59 (br tr, 1H), 1.93-1.99 (m, 1H). LCMS: M⁺446, M⁻444.

EXAMPLE 22

5-(3,5-diflurophenoxy)-2-nitropnridine

5-(3,5-Difluorophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 3,5-difluorophenol (0.35 g, 2.7 mmol) to give 210 mg ofproduct (34% yield).

¹H-NMR (CDCl₃): 8.38 (d, 1H), 8.30 (d, 1H), 7.55 (dd, 1H), 7.76 (tr tr,1H), 7.63-6.70 (m, 2H).

EXAMPLE 23

5-(3,5-diflurophenoxy)-2-pyridinamine

5-(3,5-Difluorophenoxy)-2-pyridinamine was synthesized analogously toExample 2 from 5-(3,5-difluorophenoxy)-2-nitropyridine to give about 200mg of product as brown-beige powder.

¹H-NMR (CDCl₃): 7.92 (d, 1H), 7.19 (dd, 1H), 6.54 (d, 1H), 6.39-6.51 (m,2H) 4.75 (br s, 2H).

EXAMPLE 24

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2.7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3,5-difluorophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2,5-difluorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(2,5-difluorophenoxy)-2-pyridinamine (55 mg, 0.24 mmol) to give 60 mgof pure product as white powder (61% yield).

¹H-NMR (CDCl₃): 9.70 (br s, 1H), 9.45 (br s, 1H), 7.65 (d, 1H), 7.28(dd, 1H), 6.90 (d, 1H), 6.77-6.85 (m, 1H), 6.51-6.61 (m, 2H), 6.39-6.46(m, 2H), 4.48 (dd, 1H), 4.32 (dd, 1H), 3.83 (q, 1H), 2.60 (br tr, 1H),1.94-2.10 (m, 1H).

EXAMPLE 25

5-(2,3-difluorophenoxy)-2-nitropyridine

5-(2,3-Difluorophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 2,3-difluorophenol (0.3 g, 2.7 mmol) to give 210 mg ofproduct as white powder (34% yield).

¹H-NMR (CDCl₃): 8.37 (d, 1H), 8.27 (d, 1H), 7.45 (dd, 1H), 7.13-7.23 (m,2H), 7.13-7.02 (m, 1H).

EXAMPLE 26

5-(2,3-difluorophenoxy)-2-pyridinamine

5-(2,3-Difluorophenoxy)-2-pyridinamine was synthesized analogously toExample 2 from 5-(2,3-difluorophenoxy)-2-nitropyridine (210 mg) to give180 mg of product as brown powder.

¹H-NMR (CDCl₃): 7.92 (d, 1H), 7.20 (dd, 1H), 6.84-6.99 (m, 2H),6.62-6.68 (m, 1H), 6.52 (dd, 1H), 4.40 (br s, 2H).

EXAMPLE 27

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2,3-diflurophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2,3-diflurophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(2,3-difluorophenoxy)-2-pyridinamine (55 mg, 0.24 mmol) to give 50 mgof pure product as white powder (51% yield).

¹H-NMR (CDCl₃): 9.49 (br s, ˜1H), 9.40 (br s, ˜1H), 7.58 (d, 1H), 7.27(dd, ˜1H), 9.93-7.06 (m, 2H), 6.86 (d, 1H), 6.74-6.81 (m, 1H), 6.66-6.72(m, 1H), 6.56 (tr d, 1H), 4.45 (dd, 1H), 4.32 (dd, 1H), 3.82 (q, 1H),2.59 (br tr, 1H), 1.92-1.99 (m, 1H). LC-MS: M⁺446, M⁻444.

EXAMPLE 28

5-(3,4-difluorophenoxy)-2-nitropyridine

5-(3,4-Difluorophenoxy)-2-nitropyridine was synthesized analogously toExample 1 from 3,4-difluorophenol (0.35 g, 2.7 mmol) to give 230 mg ofproduct (37% yield).

¹H-NMR (CDCl₃): 8.33 (d, 1H), 8.27 (d, 1H), 7.44 (dd, 1H), 7.23-7.31 (m,1H), 6.97-7.03 (m, 1H), 6.85-6.91 (m, 1H).

EXAMPLE 29

5-(3,4-difluorophenoxy)-2-pyridinamine

5-(3,4-Difluorophenoxy)-2-pyridinamine was synthesized analogously toExample 2 from 5-(3,4-difluorophenoxy)-2-nitropyridine (230 mg) to give160 mg of product as brown oil.

¹H-NMR (CDCl₃): 7.89 (d, 1H), 7.19 (dd, 1H), 7.07 (app q, 1H), 6.72-6.79(m, 1H), 6.61-6.67 (m, 1H), 6.54 (d, 1H), 4.46 (br s, 2H).

EXAMPLE 30

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3,4-difluorophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3,4-difluorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(3,4-difluorophenoxy)-2-pyridinamine (55 mg, 0.24 mmol) to give 60 mgof pure product as white powder (61% yield).

¹H-NMR (CDCl₃): 9.50 (br s, ˜1H), 9.45 (br s, ˜1H), 7.60 (d, 1H), 7.25(dd, ˜1H), 7.12 (app q, 1H), 6.87 (d, 1H), 6.73-6.83 (m, 2H), 6.62-6.68(m, 1H), 6.56 (tr d, 1H), 4.46 (dd, 1H), 4.32 (dd, 1H), 3.82 (q, 1H),2.60 (br tr, 1H), 1.93-2.00 (m, 1H). LC-MS: M⁺446, M⁻444.

EXAMPLE 31

2-fluoro-4-[(6-nitro-3-pyridinyl)oxy]benzonitrile

2-Fluoro-4-[(6-nitro-3-pyridinyl)oxy]benzonitrile was synthesizedanalogously to Example 1 from 2-fluoro-4-hydroxybenzonitrile (0.37 g,2.7 mmol) to give 80 mg (13% yield) of product after additionalpurification by preparative HPLC (XTerra MS C18 19×100 mm column,water/acetonitrile with 0.05% trifluoroacetic acid).

¹H-NMR (CDCl₃): 8.43 (d, 1H), 8.37 (d, 1H), 7.67-7.76 (m, 2H), 6.97-7.04(m, 2H).

EXAMPLE 32

4-[(6-amino-3-pyridinyl)oxy]-2-fluorobenzonitrile

4-[(6-amino-3-pyridinyl)oxy]-2-fluorobenzonitrile was synthesizedanalogously to Example 2 from2-fluoro-4-[(6-nitro-3-pyridinyl)oxy]benzonitrile (70 mg) to give 58 mgof product as a dark brown oil.

¹H-NMR (CDCl₃): 7.91 (d, 1H), 7.53 (dd, 1H), 7.21 (dd, 1H), 6.80 (dd,1H),6.71 (dd, 1H), 6.59 (d, 1H), 4.70 (br s, 2H).

EXAMPLE 33

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-cyano-3-fluorophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-cyano-3-fluorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from4-[(6-amino-3-pyridinyl)oxy]-2-fluorobenzonitrile (58 mg, 0.24 mmol) togive 46 mg of pure product as white powder (46% yield).

¹H-NMR (CDCl₃): 9.77 (br s, ˜1H), 9.45 (br s, ˜1H), 7.70 (d, 1H), 7.58(app tr, 1H), 7.32 (app dd, 1H), 6.93-6.99 (m, 1H), 6.75-6.85 (m, 2H),6.70 (app d tr, 1H), 6.54-6.62 (m, 1H), 4.50 (dd, 1H), 4.31 (dd, 1H),3.85 (br q, 1H), 2.63 (br tr, 1H), 1.96-2.03 (m, 1H). LC-MS: M⁺453,M⁻451.

EXAMPLE 34

2-nitro-5-(2,4,6-triflurophenoxy)pyridine

2-nitro-5-(2,4,6-trifluorophenoxy)pyridine was synthesized analogouslyto Example 1 from 2,4,6-trifluorophenol (0.4 g, 2.7 mmol) to give 310 mgof product (47% yield).

¹H-NMR (CDCl₃): 8.36 (d, 1H), 8.28 (d, 1H), 7.42 (dd, 1H), 6.89 (app tr,2H).

EXAMPLE 35

5-(2,4,6-triflurophenoxy)-2-pyridinylamine

4-[(6-amino-3-pyridinyl)oxy]-2-fluorobenzonitriie was synthesizedanalogously to Example 2 from 2-nitro-5-(2,4,6-trifluorphenoxy)pyridine(310 mg) to give 280 mg of product as brownish powder after purificationby filtration through the short pad of silica.

¹H-NMR (CDCl₃): 7.83 (d, 1H), 7.15 (dd, 1H), 6.77 (app tr, 2H), 6.48 (d,1H).

EXAMPLE 36

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2,4,6-triflurophenoxy)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(2,4,6-trifluorophenoxy)-2-pyridinyl]ureawas synthesized analogously to Example 3 from5-(2,4,6-trifluorophenoxy)-2-pyridinylamine (59 mg, 0.24 mmol) to give25 mg of pure product as white powder (24% yield).

¹ H-NMR (CDCl₃): 9.40 (br s, 1H), 9.10 (br s, 1H), 7.51 (d, 1H), 7.23(dd, 1H), 6.72-6.87 (m, 3H), 6.55 (tr d, 1H). 4.44 (dd, 1H), 4.31 (dd,1H), 3.83 (q, 1H), 2.58 (br tr, 1H), 1.91-1.98 (m, 1H). LC-MS: M⁺464,M⁻462.

EXAMPLE 37

(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-amine

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-carboxylicacid (0.5 g, 2.2 mmol, ˜95% ee) was mixed with toluene (3 ml),triethylamine (0.34 ml, 1.1 eq), DPPA (0.52 ml, 1.1 eq) and bubbled withargon for about 5 min. The reaction mixture was then heated at stirringat 120° C. for 1.5 h under argon. The temperature was then decreased to50° C. and a mixture of 3 ml of 10% hydrochloric acid in 10 ml dioxanewas added. The reaction mixture was stirred for 2 h at 50° C. and thenconcentrated by rotary evaporation. The residue was mixed with water antdiethyl ether. Water phase was collected and basified with 28% aqueousammonia to pH 11 and extracted into ether (3×20 ml). Combined organicphases were washed with water and brine and dried over magnesiumsulfate. Concentration by rotary evaporation gave 310 mg of crudeproduct as yellow orange oil. The product was purified by columnchromatography on silica (30 g, EtOAc/hexane 1:2) to give 220 mg ofcolorless oil (50% yield).

¹H-NMR (CDCl₃): 6.85 (ddd, 1H), 6.60 (tr d, 1H), 4.51 (dd, 1H), 4.33(dd, 1H), 2.97 (tr, 1H), 2.28 (app tr, 1H), 1.71 (m, 1H), 1.23 (br s,2H).

EXAMPLE 38

5-(3-fluorophenoxy)-2-isothiocyanatopyridine

5-(3-Fluorophenoxy)-2-pyridinamine (210 mg, 1 mmol) was dissolved in drydegassed methylene chloride (5 ml) and thiophosgene (0.11 ml, 1.3 mmol)was added through syringe during 5-10 min to the stirred solution.Pyridine (0.18 ml, 2 mmol) was added to the reaction mixture right afterthe addition of thiophosgene and the reaction mixture was stirred atambient temperature for 1.5-2 h. Then the reaction mixture was pouredinto water (15 ml) and extracted into methylene chloride (3×20 ml).Organic extract was washed with water and brine and dried over magnesiumsulfate. Solvent was then removed by rotary evaporation and the oilobtained was purified by column chromatography on silica (30 g,EtOAc/hexane 1:3) to give 190 mg of pure product as dark brown-purplesolid. Yield 75%.

¹H-NMR (CDCl₃): 8.20 (d, 1H), 7.30-7.37 (m, 2H), 7.10 (d, 1H), 6.89 (ddtr, 1H), 6.80 (app dd, 1H), 6.74 (d tr, 1H).

EXAMPLE 39

4-[(6-isothiocyanato-3-pyridinyl)oxy]benzonitrile

4-[(6-Isothiocyanato-3-pyridinyl)oxy]benzonitrile was synthesizedanalogously to Example 38 from 4-[(6-amino-3-pyridinyl)oxy]benzonitrile(275 mg, 1.3 mmol) to give 160 mg of pure product as brown-beige powder(49% yield).

¹H-NMR (CDCl₃): 8.25 (d, 1H), 7.67 (app d, 2H), 7.41 (dd, 1H), 7.15 (d,1H), 7.06 (app d, 2H).

EXAMPLE 40

2-isothiocyanato-5-(3-pyridinyloxy)pyridine

2-isothiocyanato-5-(3-pyridinyloxy)pyridine was synthesized analogouslyto Example 38 from 5-(3-pyridinyloxy)-2-pyridinamine (200 mg, 1 mmol) togive 110 mg of pure product as orange-pink oil (45% yield).

¹H-NMR (CDCl₃): 8.43 (tr, 1H), 8.42 (tr, 1H), 8.22 (d, 1H), 7.31-7.36(m, 3H), 7.11 (app d, 1H). LC-MS: M⁺198.

EXAMPLE 41

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-fluorophenoxy)-2-pyridinyl]thiourea

(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-amine(20 mg, 0.1 mmol) was dissolved in dry acetonitrile (1 ml) and5-(3-fluorophenoxy)-2-isothiocyanatopyridine (25 mg, 0.1 mmol) was addedand the reaction mixture was stirred at ambient temperature for 12 h.The precipitate formed was collected by filtration and washed withacetonitrile and diethyl ether to give 17 mg (38% yield) of pure productas beige powder.

¹H-NMR (CDCl₃): 8.21 (br s, 1H), 7.45 (br d, 1H), 7.28-7.34 (m, 2H),6.87 (d tr, 1H), 6.79 (tr d, 1H), 6.72 (app dd, 1H), 6.56-6.69 (m, 3H),4.46 (dd, 1H), 4.34 (dd, 1H), 4.17 (br q, 1H), 2.72 (br tr, 1H),2.06-2.13 (m, 1H).

EXAMPLE 42

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2.7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-[5-(4-cyanophenoxy)-2-pyridinyl]thiourea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-cyanophenoxy)-2-pyridinyl]thioureawas synthesized analogously to Example 41 from4-[(6-isothiocyanato-3-pyridinyl)oxy]benzonitrile (52 mg, 0.2 mmol) togive 80 mg (88% yield) of pure product as beige-white powder.

¹H-NMR (CDCl₃): 11.50 (d, 1H), 9.78 (s, 1H), 7.65 (app d, 2H), 7.53 (d,1H), 7.35 (dd, 1H), 7.00 (d, 1H), 6.98 (app d, 2H), 6.78 (d tr, 1H),6.59 (d tr, 1H), 4.48 (dd, 1H), 4.33 (dd, 1H), 4.19 (br q, 1H), 2.74 (brtr, 1H), 2.08-2.16 (m, 1H). LC-MS: M⁻449.

EXAMPLE 43

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-pyridinyloxy)-2-pyridinyl]thiourea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-pyridinyloxy)-2-pyridinyl]thioureawas synthesized analogously to Example 41 from2-isothiocyanato-5-(3-pyrdinyloxy)pyridine (58 mg, 0.25 mmol) to give 40mg (37% yield) of pure product as beige powder.

¹H-NMR (CDCl₃): 11.48 (d, 1H), 9.47 (br s, 1H), 8.42 (dd, 1H), 8.39 (d,1H), 7.45 (d, 1H), 7.32 (app dd, 2H), 7.24 (ddd, 1H), 6.90 (d, 1H), 6.78(app d tr, 1H), 6.57 (d tr, 1H) 4.46 (dd, 1H), 4.33 (dd, 1H), 4.18 (brq, 1H), 2.72 (br tr, 1H), 2.28 (app ddd, 1H) LC-MS: M⁺427, M⁻425.

EXAMPLE 43

N-[(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(pyridinyloxy)-2-pyridinyl]urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-carboxylicacid (226 mg, 1.1 mmol), 5-(pyridine-3-yloxy)-pyridine-2-ylamine, DPPA227 μL (97%) and triethylamine 140 μL were dissolved in Toluene (3 mL)and heated to reflux for 3 h. The solvent was removed and the crudeproduct was dissolved in ethyl acetate and washed with HCl_(aq) (0.01M), water and brine. Purification by chromatography (silica gel,ether-2% methanol ether-5% methanol) gave pure product (80 mg, 20%)

¹H-NMR (CDCl₃-MeOD): 9.4 (Br S, 1H), 8.49 (broad s, 1H), 8.40-8.37 (m,2H), 7.61 (d, 1H), 7.30-727 (m, 2H), 7.23-7.19 (m, 1H), 6.82-6.76 (m,2H), 6.60-6.54 (m, 1H), 4,46 (dd, 1H), 4.33 (dd, 1H), 3.80 (q, 1H), 2.60(t, 1H), 1.99-1.94 (m, 1H).

Additional Left Wings.

The following left wings are coupled to any of the above novel righthand wings analogously to Example 3 and/or 38 and/or 41 and/or with anactivated 5-substituted-pyridin-pyridin-2-yl, such as the correspondingimidazole-1-carbothioic acid (5-substituted-pyridin-2-yl)amide asdescribed in EP 540 143

EXAMPLE 44 a)±cis-1,1a,2,7b-Tetrahydro-cyclopropa[c]chromene-1-carboxylic acid ethylester

To a mixture of 2H-chromene (4.89 g, 37 mmol) and (CuOTf)₂-benzene (186mg, 0.37

mmol) in 1,2-dichloroethane (80 mL) at 20° C., was added dropwise (3 h)a solution of ethyl diazoacetate (8.44 g, 74 mmol) in 1,2-dichloroethane(20 mL). After 15 min at 20° C., the reaction mixture was washed withH₂O (100 mL). The H₂O phase was washed with CH₂Cl₂ (50 mL) and thesolvent of the combined organic phases was removed under reducedpressure. The crude product was column chromatographed (silica gel,20→50% EtOAc in hexane), to give 1.96 g (24%) of±cis-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid ethylester and 3.87-g (48%) of±-trans-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acidethyl ester as a by product.

¹H-NMR (CDCl₃): 7.26 (d, 1H), 7.10 (dd, 1H), 6.90 (dd, 1H), 6.78 (d,1H), 4.49 (dd, 1H), 4.20 (dd, 1H), 3.97 (q, 2H), 2.44 (dd, 1H), 2.14(dd, 1H), 2.07-1.95 (m, 1H), 1.02 (t, 3H).

b) (±)-cis-1,1a,2,7b-Tetrahydro-cyclopropa[c]chromene-1-carboxylic acid

A mixture of(±)-cis-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acidethyl ester (1.96 g, 9.0 mmol), LiOH (539 mg, 22.5 mmol), H₂0 (10 mL)and MeOH (20 mL) was heated to reflux for 2 h. The reaction mixture wasconcentrated to about 10 mL, 4N HCl was added dropwise giving a whiteprecipitate. The reaction mixture was extracted with CH₂Cl₂ (3×15 mL)and the solvent of the combined organic phases was removed under reducedpressure. The crude product was crystallized from EtOAc/hexane, to give435 mg (25%) of(±)-cis-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid asa white solid.

¹H-NMR (CDCl₃): 9.80 (br s, 1H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.89 (dd,1H), 6.77 (d, 1H), 4.45 (dd, 1H), 4.22 (dd, 1H), 2.45 (dd, 1H),2.14-1.98 (m, 2H).

EXAMPLE 45 a)(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid ethyl ester

(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cyclopropa[c]naphthalene-1-carboxylicacid ethyl ester was synthesized analogously to Example 44a from1H-isochromene (3.57 g, 27 mmol), to give 910 mg (15%) of(±)-cis-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 7.34 (d, 1H), 7.25 (dd, 1H), 7.18 (dd, 1H), 7.03 (d,1H), 4.81 (d, 1H), 4.51 (d, 1H), 4.28 (dd, 1H), 3.95 (q, 2H), 2.43 (dd,1H), 2.05 (dd, 1H), 1.04 (t, 3H).

b)(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cylopropa[a]naphthalene-1-carboxylicacid

(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid was synthesized analogously to Example 44b from(±)-cis-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid ethyl ester (436 mg, 2 mmol), to give 86 mg (22%) of(±)-cis-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid as a white solid. The crude product was column chromatographed(silica gel, 1→5% MeOH in CH₂Cl₂).

¹H-NMR (CDCl₃): 8.50 (br s, 1H), 7.39 (d, 1H), 7.30 (dd, 1H), 7.21 (dd,1H), 7.07 (d, 1H), 4.87 (d, 1H), 4.57 (d, 1H), 4.38 (dd, 1H), 2.59 (dd,1H), 2.15 (dd, 1H).

The product of step b

EXAMPLE 46(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-ureaa) 1-(2-Hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one

A mixture of 2′,4′-dihydroxy-propiophenone (24.9 g, 0.15 mol),3-bromo-propyne (24.2 g, 0.20 mol) and K₂CO₃ (20.7 g, 0.15 mol) inacetone (500 mL) was refluxed for 12 h. The reaction mixture was allowedassume room temperature and the precipitate was removed by filtration.The filtrate was concentrated under reduced pressure. The crude productwas purified by column chromatography (silica gel, 0→2% MeOH in H₂O), togive 26.2 g (85%) of 1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one.

¹H-NMR (CDCl₃): 12.80 (s, 1H), 7.69 (d, 1H), 6.52 (m, 2H), 4.72 (d, 2H),2.96 (q, 2H), 2.56 (t, 1H), 1.23 (t, 3H).

3b) 1-(5-Hydroxy-2H-chromen-6-yl)-propan-1-one

A mixture of 1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one (19.8 g,97 mmol) and N,N-diethylaniline (100 mL) was heated to reflux for 3 h.The reaction mixture was concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica gel, 5-10% EtOAcin Hexane) and thereafter recrystallized from EtOAc/Hexane, to give 8.91g (45%) of 1-(5-hydroxy-2H-chromen-6-yl)-propan-1-one.

¹H-NMR (CDCl₃): 13.00 (s, 1H), 7.49 (d, 1H), 6.75 (dt, 1H), 6.27 (d,1H), 5.67 (dt, 1H), 4.86 (dd, 2H), 2.90 (q, 2H), 1.19 (t, 3H).

3c)7-Hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

To a mixture of 1-(5-hydroxy-2H-chromen-6yl)-propan-1-one (511 mg, 2.5mmol) and (Rh(II)Ac₂)₂ (11 mg, 0.025 mmol) in 1,2-dichloroethane (8 mL)at 20° C., was added dropwise (3 h) a solution of ethyl diazoacetate(571 mg, 5 mmol) in 1,2-dichloroethane (2 mL). After 15 min at 20° C.,the reaction mixture was washed with H₂O (10 mL). The H₂O phase waswashed with CH₂Cl₂ (10 mL) and the solvent of the combined organicphases was removed under reduced pressure. The crude product waspurified by column chromatography (silica gel, 1→5% MeOH in CH₂Cl₂), togive 300 mg (41%) of7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (a 33/64 mixture of cis and trans isomers).

¹H-NMR (CDCl₃): 13.13-13.07 (m, 1H), 7.57-7.49 (m, 1H), 6.41-6.38 (m,1H), 4.65-3.92 (m, 4H), 3.01-1.95 (m, 5H), 1.29-1.08 (m, 6H).

3d)(±)-cis-7-Hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

±cis-7-Hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 2b from7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (299 mg, 1.03 mmol, a 33/64 mixture of cis and transisomers), to give 39.3 mg (15%) of(±)-cis-7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid as a white solid and(±)-trans-7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid as a byproduct. The crude product was purified by columnchromatography (silica gel, 1→5% MeOH in CH₂Cl₂).

¹H-NMR (DMSO-d₆): 7.67 (d, 1H), 6.35 (d, 1H), 4.57 (dd, 1H), 4.36 (dd,1H), 2.98 (q, 2H), 2.55-2.46 (m, 1H), 2.18-2.00 (m, 2H), 1.10 (t, 3H).

EXAMPLE 47 a) 1-(2-Hydroxy-4-prop-2-ynyloxy-phenyl)-ethanone

1-(2-Hydroxy-4-prop-2-ynyloxy-phenyl)-ethanone was synthesizedanalogously to Example 46a from 1-(2,4-dihydroxy-phenyl)-ethanone (20 g,131 mmol), to give 22 g (88%) of1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-ethanone.

¹H-NMR (CDCl₃): 12.70 (s, 1H), 7.66 (d, 1H), 6.52 (m, 2H), 4.72 (d, 2H),2.58-2.55 (m, 4H).

b) 1-(5-Hydroxy-2H-chromen-6-yl)-ethanone

1-(5-Hydroxy-2H-chromen-6-yl)-ethanone was synthesized analogously toExample 46b from 1-(2-hydroxyprop-2-ynyloxy-phenyl)-ethanone (17 g, 89mmol), to give 6.0 g (35%) of 1-(5-hydroxy-2H-chromen-6-yl)-ethanone.

¹H-NMR (CDCl₃): 12.92 (s, 1H), 7.51 (d, 1H), 6.79 (dt, 1H), 6.32 (d,1H), 5.71 (dt, 1H) 4.89 (dd, 2H), 2.55 (s, 3H).

4c)6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (a 40/60 mixture of cis and trans isomers) wassynthesized analogously to Example 46c from1-(5-hydroxy-2H-chromen-6-yl)-ethanone.

¹H-NMR (CDCl₃): 13.05-12.97 (m, 1H), 7.54-7.47 (m, 1H), 6.43-6.33 (m, 1H), 4.63-3.94 (m, 4H), 3.02-1.96 (m, 6H), 1.31-1.08 (m, 3H).

d)6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 44b from6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (2 g, 8.1 mmol, a 40/60 mixture of cis and transisomers), to give 300 mg (17%) of6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (a 40/60 mixture of cis and trans isomers). The crude product waspurified by column chromatography (silica gel, 1→5% MeOH in CH₂Cl₂)

¹H-NMR (CDCl₃): 7.55-7.45 (m, 1H), 6.45-6.30 (m, 1H), 4.65-4.00 (m, 2H),3.05-1.95 (m, 6H).

EXAMPLE 48 5a) 1-(4-Fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one

To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 mL) at 0° C., wasadded 1-(4-fluoro-2-hydroxy-phenyl)-propan-1-one (1.68 g, 10 mmol) inDMF (5 mL). After 15 min at 0° C., was 3-bromo-propyne (3.02 g, 20 mmol)added to the reaction mixture. After 1 h at 0° C., was the reactionmixture allowed to assume room temperature. The reaction mixture wasextracted with H₂O (100 mL). The H₂O phase was washed with Et₂O 3×100mL) and the solvent of the combined organic phases was removed underreduced pressure. The crude product was purified by columnchromatography (silica gel, CH₂Cl₂), to give 1.40 g (68%) of1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.

¹H-NMR (CDCl₃): 7.64 (dd, 1H), 6.69 (dd, 1H), 6.60 (ddd, 1H), 4.68 (d,2H),2.85 (q, 2H), 2.58 (t, 1H), 1.03 (t, 3H).

b) 1-(5-Fluoro-2H-chromen-8-ylpropan-1-one

1-(5-Fluoro-2H-chromen-8-yl)-propan-1-one was synthesized analagously toExample 46b from 1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one (1.34g, 6.5 mmol), to give 619 mg (46%) of1-(5-fluoro-2H-chromen-8-yl)-propan-1-one.

¹H-NMR (CDCl₃): 7.60 (dd, 1H), 6.67-6.58 (m, 2H), 5.86 (dt, 1H), 4.76(dd, 2H), 2.93 (q, 2H), 1.23 (t, 3H).

c)(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester was synthesized according to method 46c) from1-(5-fluoro-2H-chromen-8-yl)-propan-1-one (619 mg, 3 mmol), to give 142mg (16%) of(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester and(±)-trans-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester as a byproduct.

¹H-NMR (CDCl₃): 7.59 (dd, 1H), 6.65 (m, 1H), 4.50-4.46 (m, 2H), 3.95 (q,2H), 2.89 (q, 2H), 2.57 (dd, 1H), 2.20 (dd, 1H), 1.13-1.03 (m, 1H),1.12-1.01 (m, 6H).

5d)(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 44b from(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (140.3 mg, 0.48 mmol). to give 83 mg (65%) of(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid as a white solid. The crude product was purified by columnchromatography (silica gel, 1→5% MeOH in CH₂Cl₂).

¹H-NMR (DMSO-d₆): 12.15 (br s, 1H), 7.46 (dd, 1H), 6.78 (dd, 1H), 4.57(dd, 1H), 4.43 (dd, 1H), 2.93-2.80 (m, 2H), 2.55 (dd, 1H), 2.24 (dd,1H), 2.20-2.10 (m, 1H), 1.02 (t, 3H).

EXAMPLE 49 a) 6-Fluoro-2-hydroxy-3-methoxy-benzaldehyde

1M boron trichloride in dichloromethane (25 ml; 25 mmol) was added to asolution of 6-fluoro-2,3-dimethoxy-benzaldehyde [Cantrell, Amanda S.;Engelhardt, Per; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, NilsGunnar; et al.; J. Med. Chem.; 39; 21; 1996; 4261-4274] (4.26 g; 23mmol) in dichloromethane (30 ml) keeping the reaction temperature at −70C. The reaction mixture stirred at room temperature overnight andhydrolyzed with water. The organic phase was separated, washed withwater and evaporated in vacuc. The residue was chromatographed (silicagel, EA:Hex, 5:1) to give 3.72 g (94%) of6-fluoro-2-hydroxy-3-methoxy-benzaldehyde as yellow crystals.

¹H-NMR (CDCl₃): 11.61 (s, 1H), 10.23 (s, 1H), 7.02 (dd, 1H), 6.55 (app.t, 1H), 3.87 (s, 3H).

b) 5-Fluoro-8-methoxy-2H-chromene

6-Fluoro-2-hydroxy-3-methoxy-benzaldehyde (3.32 g, 19 mmol) wasdissolved in acetonitrile (20 ml) and DBU (2.97 ml, 19 mmol) was-addedfollowed by vinyltriphenylphosphine bromide (7.2 g, 19 mmol). Thereaction mixture was heated under reflux for 48 h, diluted with waterand extracted with ether (3×50 ml). The organic phase was washed withwater, 10% sodium hydroxide, water and brine and evaporated in vacuo.The residue was submitted to column chromatography (silica gel, EA:Hex,1:20) yielding 1.2 g of 5-fluoro-8-methoxy-2H-chromene (34%).

¹H-NNMR (CDCl₃): 6.65 (m, 2H), 6.54 (t, 1H), 5.83 (dt, 1H), 4.88 (dd,2H), 3.83 (s, 3H).

c)(±)-cis-7-Fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

The title compound was synthesized analogously to example 46c from5-fluoro-8-methoxy-2H-chromene.

¹H-NMR (CDCl₃): 6.7-6.5 (m, 2H), 4.48 (m, 2H), 3.99 (m, 2H), 3.80 (s,3H), 2.57 (app. t, 1H), 2.20 (app. t, 1H), 2.05 (m, 1H), 1.08 (t, 3H).

d)(±)-cis-7-Fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

The title compound was synthesized analogously to example 44b from(±)-cis-7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 6.7-6.5 (m, 2H), 4.48 (m, 2H), 3.80 (s, 3H), 2.61 (app.t, 1H), 2.17 (app. t, 1H), 2.06 (m, 1H).

e)(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

The title compound was synthesized analogously to Example 44c from(±)-cis-7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (62 mg, 0.17 mmol). Yield 38 mg (40%).

¹H-NMR (CDCl₃): 10.06 (br. s, 1H), 9.40 (br. d, 1H), 8.11 (d, 1H), 7.70(dd, 1H), 6.91 (d, 1H), 6.68 (m, 2H), 4.48 (dd, 1H), 4.28 (dd, 1H),3.90-3.72 (m, 4H), 2.64 (app. T. 1H), 1.96 (m, 1H).

EXAMPLE 50 a) 1-Chloro-4-fluoro-2-prop-2-ynyloxy-benzene

The title compound was synthesized analogously to example 15a) from2-chloro-5-flurophenol (2.5 g). Yield 2.8 g (90%).

¹H-NMR (CDCl₃): 7.32 (dd, 1H), 6.85 (dd, 1H), 6.68 (m, 1H), 4.77 (d,2H), 2.58 (t, 1H).

7b) 5-Fluoro-8-chloro-2H-chromene

The title compound was synthesized analogously to Example 15b) from1-chloro-4-fluoro-2-prop-2-ynyloxy-benzene (2.8 g). Yield 0.97 g (35%).

¹H-NMR (CDCl₃): 7.09 (dd, 1H), 6.63 (dt, 1H), 6.56 (t, 1H), 5.84 (dt,1H), 4.95 (dd, 2H).

c)±cis-7-Fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

The title compound was synthesized analogously to Example 15c) from5-Fluoro-8-chloro-2H-chromene.

¹H-NMR (CDCl₃): 7.14 (dd, 1H), 6.60 (t, 1H), 4.51 (m, 2H), 4.01 (m, 2H),2.60 (app. t, 1H), 2.23 (t, 1H), 2.09 (m, 1H), 1.08 (t, 3H).

d)(±)-cis-7-Fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

The title compound was synthesized analogously to example 15 d) from(±)-cis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester 850 mg). Yield 43 mg (96%).

¹H-NMR (CDCl₃): 8.86 (br. s, 1H), 7.13 (dd, 1H), 6.59 (t, 1H), 4.50 (m,2H), 2.63 (t, 1H), 2.23-2.05 (m, 2H).

EXAMPLE 51 a) Trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenylester

A solution of triflic anhydride (1.77 ml, 10.5 mmol) in dichloromethane10 ml) was added to a mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 10mmol) and pyridine (0.85 ml, 10.5 mmol) in dichloromethane (30 ml) at−70 C. Dry ice bath was removed and the reaction mixture was stirred for2 h at room temperature. The reaction mixture was diluted withdichloromethane, washed with water, brine and evaporated in vacuo. Thecrude product was purified by column chromatography (silica gel, EA:Hex,1:6) to give 1.55 g of trifluoro-methanesulfonic acid4-formyl-3-hydroxy-phenyl ester (57%).

¹H-NMR (CDCl₃): 11.28 (s, 1H), 9.93 (s, 1H), 7.67 (d, 1H), 6.95 (m, 2H).

b) Trifluoro-methanesulfonic acid 3-allyloxy-4-formyl-phenyl ester

Potassium carbonate (1.6 g, 11.5 mmol) and allyl bromide (1 ml, 11.5mmol) were added to a solution of trifluoro-methanesulfonic acid4-formyl-3-hydroxy-phenyl ester (1.55 g, 5.7 mmol) in acetone (50 ml).The reaction mixture was stirred at 55 C for 2 h, filtered andevaporated in vacuo. The residue was chromatographed (silica gel,EA:Hex, 1:20) to give 1.3 g (73%) of trifluoro-methanesulfonic acid3-allyloxy-4-formyl-phenyl ester.

¹H-NMR (CDCl₃): 10.47 (s, 1H), 7.93 (d, 1H), 6.95 (d, 1H), 6.90 (s, 1H),6.05 (m, 1H), 5.47 (d, 1H), 5.40 (d, 1H), 4.69 (d, 2H).

c) Trifluoro-methanesulfonic acid 3-allyloxy-4-vinyl-phenyl ester

Methyltriphenylphosphonium bromide (1.95 g, 5.45 mmol) was added to asuspension of sodium hydride (60% in oil) (0.25 g, 6.3 mmol) in THF (35ml) at 0 C and it was stirred for 30 min at room temperature. To theabove solution was added solution of trifluoro-methanesulfonic acid3-allyloxy-4-formyl-phenyl ester (1.3 g, 4.2 mmol) in THF (15 ml), ndthe reaction mixture was stirred for 2 h at room temperature. Thereaction mixture as diluted with hexane and extracted with water.Organic phase was washed with brine and evaporated. Silica gel columnchromiatography (EA:Hex, 1:20) afforded trifluoromethanesulfonic acid3-allyloxy-4-vinyl-phenyl ester (0.68 g, 53%).

¹H-NMR (CDCl₃): 7.51 (d, 1H), 7.02 (dd, 1H), 6.85 (dd, 1H), 6.77 (d,1H), 6.05 (m, 1H), 5.76 (dd, 1H), 5.43 (m, 1H), 5.32 (m, 2H), 4.58 (dt,2H).

d) Trifluoro-methanesulfonic acid 2H-chromen-7-yl ester

To a solution of trifluoro-methanesulfonic acid3-allyloxy-4-vinyl-phenyl ester (0.68 g, 2.2 mmol) in dichloromethane (5ml) was added Ru-catalyst (Grubb's catalyst) (36 mg, 2 mol %), and thereaction mixture was stirred for 2 h at room temperature. After thatperiod the reaction was complete (GC) and the reaction mixture was usedin the next step without any work-up. Analytical sample was obtainedafter removal of the solvent by silica gel column chromatography(EA:Hex, 1:20).

¹H-NMR (CDCl₃): 6.97 (d 1H), 6.76 (dd, 1H), 6.68 (d, 1H), 6.39 (dt, 1H),5.81 (dt, 1H), 4.98 (dd, 2H).

e)(±)-cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

Rh(OAc)₂ (19 mg, 2 mol %) was added to the above solution (10d) and thesolution of EDA (0.44 ml, 4.4 mmol) in 1 ml of dichloromethane was addedwith a syringe pump over 5 h at room temperature. When the reaction wascomplete (GC) dichloromethane was evaporated, the residue was dissolvedin ethyl acetate and washed with saturated ammonium chloride solutionand brine. Organic phase was evaporated and crude mixture of cis andtrans-isomers (1:1.3) was separated by column chromatography (silicagel, EA:Hex, 1:6) to give 0.4 g (50%) of±cis-5-trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 7.29 (d, 1H), 6.82 (dd, 1H), 6.73 (d, 1H), 4.51 (dd,1H), 4.29 (dd, 1H), 3.98 (m, 2H), 2.45 (t, 1H), 2.19 (t, 1H), 2.05 (m,1H), 1.03 (t, 3H).

f) ±cis-5-Cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene1-carboxylicacid ethyl ester

±cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (154 mg, 0.42 mmol), Pd(OAc)₂ (9 mg, 10 mol %) and PPh₃(44 mg, 40 mol %) were mixed in DMF (4 ml) and gentle stream of nitrogenpassed through reaction mixture for 10 min. Zn(CN)₂ (74 mg, 0.63 mmol)was added, vial was sealed and the reaction mixture was stirred at 120 Covernight. The reaction mixture was diluted with ethyl acetate andextracted with saturated ammonium chloride. Organic phase was evaporatedand residue chromatographed (silica gel, EA:Hex 1:5) to give 53 mg (52%)of ±cis-5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxyiicacid ethyl ester.

¹H-NMR (CDCl₃): 7.33 (d, 1H), 7.19 (dd, 1H), 7.05 (d, 1H), 4.50 (dd,1H), 4.25 (dd, 1H), 3.99 (q, 2H), 2.46 (t, 1H), 2.25 (t, 1H), 2.11 (m,1H), 1.06 (t, 3H).

g) ±cis-5-Cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

±cis-5-Cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (53 mg, 0.22 mmol) and NaOH (35 mg, 0.88 mmol) weredissolved in mixture methanol water (1:1) (5 ml). Reaction mixture wasstirred at 60 C for 30 min. Methanol was evaporated in vacuo and 20 mlof water was added. Resulting solution was extracted with ether. Waterphase was concentrated, acidified with 1M HCl to pH˜12 and extractedwith ether. The organic phase was washed with brine and evaporated togive 42 mg (90%) of±cis-5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

¹H-NMR (CDCl₃): 7.33 (d, 1H), 7.19 (dd, 1H), 7.06 (d, 1H), 4.51 (dd,1H), 4.31 (dd, 1H), 2.53 (app. t, 1H), 2.27 (app. t, 1H), 2.16 (m, 1H).

EXAMPLE 52 a)±cis-5-Trimethylsilanylethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

±cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (152 mg, 0.41 mmol), DPPP (38 mg, 20 mol %), Pd(dba)₂(24 mg, 10 mol %), CuI (3 mg, 4 mol %) were mixed in 3 ml oftriethylariine and gentle stream of nitrogen passed through reactionmixture for 10 min. Trimethylsilyl-acetylene (0.088 ml, 0.62 mmol) wasadded, vial was sealed and the reaction mixture was stirred at 120 Covernight. The reaction mixture was diluted with ethyl acetate, washedwith water, brine and evaporated. The residue was purified by silica gelcolumn chromatography (EA:Hex, 1:15) to give 0.1 g (77%) of±cis-5trimethylsilanylethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 7.15 (d, 1H), 7.01 (dd, 1H), 6.88 (d, 1H), 4.47 (dd,1H), 4.16 (dd, 1H), 3.96 (q, 2H), 2.38 (t, 1H), 2.13 (t, 1H), 2.01 (m,1H), 1.04 (t, 3H), 0.22 (s, 9H).

b)±cis-5-Ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

±cis-5-Trimethylsilanylethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (0.1 g, 0.32 mmol) and sodium hydroxide (0.076 g, 1.9mmol) were dissolved in mixture of methanol:water (1:1) (5 ml). Thereaction mixture was heated at 60 C for 5 h, then it was acidified with1 M HCl to pH˜2 and extracted with ether. The organic phase was washedwith brine and evaporated to give 66 mg (97%) of±cis-5-ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

¹H-NMR (CDCl₃): 7.17 (d, 1H), 7.03 (dd, 1H), 6.91 (d, 1H), 4.45 (dd,1H), 4.23 (dd, 1H), 3.02 (s, 1H), 2.46 (t, 1H), 2.13 (t, 1H), 2.07 (m,1H).

EXAMPLE 53±cis-1-(5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-ureaa) ±cis-5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

±cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (117 mg, 0.32 mmol), DPPP (7.3 mg, 50 mol %), Pd(OAc)₂(2 mg, 25 mol %) and triethyl amine (0.09 ml, 0.64 mmol) were mixed inDMF (3 ml) and gentle stream of nitrogen passed through reaction mixturefor 10 min. Butyl vinyl ether (0.21 ml, 1.6 mmol) was added, vial wassealed and the reaction mixture was stirred at 100 C for 2 h. 5% HCl (5ml) was added and the reaction mixture was stirred at room temperaturefor 30 min. Resulting mixture was extracted with ethyl acetate. Theorganic phase was washed with saturated ammonium chloride andevaporated. The residue was purified by silica gel column chromatography(EA:Hex, 1:5) to give 76 mg (91%) of±cis-5-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃):7.52 (dd, 1H), 7.36 (d, 1H), 7.34 (d, 1H), 4.51 (dd, 1H),4.21 (dd, 1H), 3.98 (q, 2H), 2.53 (s, 3H), 2.47 (t, 1H), 2.23 (t, 1H),208 (m, 1H), 1.05(t, 3H).

b) ±cis-5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

The title compound was synthesized analogously to example 51 g from±cis-5-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (76 mg, 29 mmol). Yield 66 mg (97%).

¹H-NMR (CDCl₃): 7.52 (dd, 1H), 7.37 (d, 1H), 7.34 (d, 1H), 4.52 (dd,1H), 4.26 (dd, 1H), 2.55 (s, 3H ), 2.53 (t, 1H), 2.25 (t, 1H), 2.13 (m,1H).

EXAMPLE 54±cis-5-Methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

The title compound was synthesized analogously to example 51 from2-hydroxy-4-methoxybenzaldehyde.

EXAMPLE 55 a) N-Acetyl-1,2-dihydroquinoline

Quinoline (19.37 g, 150 mmol) was dissolved in anhydrous diethyl ether(500 ml) and cooled to 0° C. under inert atmosphere. DIBAL, 1.5 M intoluene (100 ml, 150 mmol) was added dropwise over 2 hrs and thereaction mixture was stirred at 0° C. for 30 min. Acetic anhydride (500ml) was added dropwise over 30 min and the reaction mixture was stirredat 0° C. for 30 min. H₂O was added cautiously. The reaction mixture wasextracted with diethyl ether and concentrated to giveN-acetyl-1,2-dihydroquinoline (11.5 g, 44%).

b)±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester

±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester was prepared according to the procedure described inexample 44a, from N-acetyl-1,2-dihydroquinoline (10 g, 58 mmol) Theproduct was purified by column chromatography on silica (EtOAc/hexane5%→50%) to give±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester (2.0 g, 13%).

c)±cis-(N-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid

±cis-(N-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid (425 mg, 24%) was prepared according to the procedure described inexample 44b, from±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester (2.0 mg, 7.7 mmol).

EXAMPLE 56 a) 2,4-Difluoro-2-propynyloxybenzene

Commercially available 2,5-difluorophenol (20 g, 0.15 mol), K₂CO₃ (53 g,0.38 mol) and commercially available 3-bromopropyne (45 g, 0.38 mol)were dissolved in acetone (300 ml), refluxed over night, cooled andfiltrated. The solvent was removed and the crude product, dissolved inether and washed with water and brine. The organic phase was evaporatedand the crude product was re-dissolved in a small amount of ether andfiltrated through a column of basic Al₂O₃. Evaporation and drying gave20 g (80%) of 2,4-difluoro-2-prop-ynyloxy-benzene

b) 5,8-Difluoro-2H-chromene

2,4-Difluoro-2-propynyloxybenzene (20 g, 0.12 mol) was dissolved inN,N,-diethyl aniline (100 ml) and heated under argon atmosphere at 225deg. Celcius with an oil-bath for 6-8 h. Ether (150 ml) was added andthe aniline was removed by extraction using 2 M HCl_((aq)). Purificationby chromatography (silica gel, n-hexane) gave5,8-difluoro-2H-chromene.5.8 g (29%)

c)+/−cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

5,8-Difluoro-2H-chromene (5 g, 0.03 mol), (Rh(II)Ac₂)₂ (0.39 g, 0.00089mol) was dissolved in 1,2-dichloroethane (60 ml) or ethanol-freechloroform. Ethyl diazoacetate (9.4 ml, 0089 mol) in the same solventwas added dropwise over a period of approximately 5 h under N₂atmosphere. The solvent was then removed under vacuum and the mixturewas taken upp in ethyl acetate, washed with NaHCO₃(aq), water and brineand the solvent removed. The product (33% cis, 66% trans) was purifiedby hromatography (0→10% ethyl acetate in n-hexane) to give 2.2 g of thetitle compound (30%).

d)cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

Cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (2 g, 0.008 mol) was heated in 1M LiOH inmethanol-water (25%) at 80 deg. for 2 h. The volume was reduced to halfand acidified. Extraction with ether followed by chromatography (silicagel, ether) gave pure title compound (35%)

EXAMPLE 57

Additional Intermediates

a) 6-Fluorochroman-4-ol

6-Fluorochroman-4-one (10 g, 61 mmol) was dissolved in ethanol (100 ml).NaBH₄ (excess) was added and cooled on icebath. The mixture was thenleft in room temperature for 2 h, followed by reflux for 4 h.Purification by chromatography (silica gel, ether-hexane, 1:5) gave 8. g(80%) pure 6-fluoro-chroman-4-ol.

b) 6-Fluoro-2H-chromene

6-Fluorochroman-4-ol (8 g, 48 mmol) and toluene-4-sulphonic acid (1 g)were dissolved in toluene and refluxed over-night with subsequent waterremoval. The mixture was then cooled and washed with NaHCO₃ (aq) andpurified by chromatography (silica gel, n-hexane) to give 4.2 g (52%) ofpure 6-fluoro-2H-chromene.

c)+/−cis-6-Fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

This Compound was prepared analogously tocis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 6-fluoro-2H-chromene to give 1.9 (29%) of thetide compound.

d) Cis-6-Fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

This compound was prepared analogously tocis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]

chromene-1-carboxylic acid but usingcis-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (1.9 g, 8 mmol) to give 350 mg (21%) of purecis-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

e) 1-Bromo-4-fluoro-2-prop-2-ynyloxy-benzene

This compound was prepared analogously to2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-5-fluorphenol (15g, 78 mmol) to give 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene 15.6 g(87%)

f) 2-Bromo-4-fluoro-1-prop-2-ynyloxy-benzene

This compound was prepared analogously to2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-4-fluoro-phenol(15 g, 78 mmol) to give 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene 15. g(84%).

g) 1,3-difluoro-5-prop-2-ynyloxy-benzene

This compound was prepared analogously to2,4-difluoro-2-propynyloxybenzene but using 3,5-difluoro-phenol (14 g,107 mmol) to give 1,3-difluoro-5-prop-2-ynyloxy-benzene 12 g (67%).

h) 8-Bromo-6-fluoro-2H-chromene

This compound was prepared analogously to 5,8-difluoro-2H-chromene butusing (15 g, 65 mmol) of 2-bromo-4-fluoro-1-prop-2-ynyloxybenzene togive the title compound (7 g, 46%)

i) 8-Bromo-5-fluoro-2H-chromene

This compound was prepared analogously to 5,8-difluoro-2H-chromene butusing (15 g, 65 mmol) of 1-bromo-4-fluoro-2-prop-2-ynyloxybenzene togive the title compound (3.7 g, 25%)

j) 5,7-Difluoro-2H-chromene

This compound was prepared analogously to 5,8-difluoro-2H-chromene butusing (18 g, 107 mmol) of 1,3-difluoro-5-prop-2-ynyloxybenzene andPEG-200 as solvent to give the title compound (4 g, 23%).

k)+/−cis-4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

This compound was prepared analogously to+/−cis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 5 g (22 mmol) of 8-bromo-6-fluoro-2H-chromeneto give 1.9 g (30%) ofcis-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

l)+/−cis-4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

This compound was prepared analogously to+/−cis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 3.5 g (15.3 mmol) of8-bromo-5-fluoro-2H-chromene to give 1.6 g (33%) of+/−cis-4-bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

m)+/−cis-5,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

This compound was prepared analogously to+/−cis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 2 g (12 mmol) of 5,7-difluoro-2H-chromene-togive 0.9 g (29%) of +/−cis-5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid ethyl ester.

EXAMPLE 58 a) Resolution of the racemiccis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

0.32 g (1.32 mmol) of racemiccis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was dissolved in hot acetonitrile (50 ml) and(1R,2R)-2-benzyloxycyclopentylamine (0.25 g, 1.32 mmol) was-added. Theresulting solution was left for crystallization. After few hours themother liquor was decanted and crystals were washed with acetonitrile.The second crystallization from acetonitrile gave 92 mg of purediastereomeric salt. The salt was treated with 1 M HCl and resultingmixture was extracted with ethyl acetate. The organic phase was washedwith water, brine and evaporated to give 0.05 g of enantiomericcis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

EXAMPLE 59 +/−cis-N-(5-cyano-2-pyridinyl)-N′-(4,7-dichloro-1,1a,27b-tetraydrocyclopropa[c]chromen-1-yl)urea a)1,4-dichloro-2-(2-propynyloxy)benzene

2,5-Dichlorophenol (8 g, 49 mmol) was mixed with potassium carbonate(13.6 g, 98 mmol) and 80% solution of propargyl bromide in toluene (11ml, 98 mmol) in acetone (100 ml) and stirred overnight at roomtemperature. The precipitate was removed by filtration and washed withacetone. The acetone solution obtained was concentrated by rotaryevaporation and kept under vacuum for 5 h. The product was obtained asyellow oil with quantitative yield. It was used for furthertransformations without additional purification.

b) 5,8-dichloro-2H-chromene

1,4-Dichloro-2-(2-propynyloxy)benzene was degassed and heated atstirring under argon for 4 h at 224° C. The reaction mixture was thendistilled in Kugelrohr apparatus (150-175° C./4.1×10⁻² mbar) to give3.58 g of desired product as white solid. Yield 36% from startingdichlorophenol.

c)+/−cis-ethyl-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate

5,8-Dichloro-2H-chromene (3.15 g, 16 mmol), (Rh(II)Ac₂)₂ (30 mg, 0.1 mol%) was dissolved in degassed dry methylene chloride (3 ml). Ethyldiazoacetate (3 ml, 2 eq.) in the same solvent was added by a syringe atthe flow rate 0.4 ml/h over a period of approximately 5 h under N₂atmosphere. The reaction mixture was then washed with NH₄Cl(aq), waterand brine and the solvent removed. The product (45% cis, 55% trans) waspurified by chromatography on silica (200 g, ethyl acetate/n-hexane1:15) to give 0.9 g of the pure cis product (racemate). Yield 20%.M⁺=287.

¹H-NMR (CDCl₃): 7.15 (d, 1H, J=8.5 Hz), 6.91 (d, 1H, J=8.8 Hz), 4.59(dd, 1H, J₁=12.02, J₂=7.03), 4.48 (dd, 1H, J₁=12.02, J₂=4.10), 4.07-3.94(m, 3H), 2.62 (t, 1H, J=8.8 Hz), 2.27 (t, 1H, J=8.36 Hz), 2.20-2.12 (m,1H), 1.1 (t, 3H).

d)+/−cis-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid

+/−cis-Ethyl-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylatewas mixed with methanol (3 ml) and water solution of NaOH (1.5 eq., 3ml) and heated at stirring for 1.5 h at 60° C. The extraction of basicreaction mixture into hexane showed that no starting material present.The reaction mixture was acidified with excess of 3M HCl solution(pH=1). The precipitate formed was collected by suction and washed withwater. White solid obtained was dried under high vacuum (yield 80%).

EXAMPLE 59A a) 5-chloro-2-fluorophenol

5-Chloro-2-fluoroaniline (10 g, 68 mmol) was dissolved in 6M sulfuricacid and cooled in ice/brine bath to −5° C. The solution of NaNO₂ (5.2g, 76 mmol) in minimum amount of water was added dropwise to the stirredsuspension at the temperature not higher then −2° C. After the additionclear yellow solution formed was allowed to stir for additional 30 minat cooling. CuSO₄ was dissolved water (80 ml) and mixed with sulfuricacid (32 ml). The diazonium salt solution was added dropwise to thepreheated (160° C.) cuprous sulfate solution and the product was removedfrom the reaction flask by steam distillation. The reaction took about 2h to be complete. The water/phnol solution was extracted into ether,washed with brine and dried over Na₂SO₄. Concentration gave 4 g of crudephenol (40%).

b) 4-chloro-1-fluoro-2-(2-propynyloxy)benzene

4-Chloro-1-fluoro-2-(2-propynyloxy)benzene was synthesized analogouslyto Example 33a from (4 g, 27 mmol) 4-chloro-1-fluorophenol to give 4.6 gof product (purified by column chromatography on silica, ethylacetate/n-hexane 1:15) as yellow oil. Yield 90%.

c) 5-chloro-8-fluoro-2H-chromene

5-Chloro-8-fluoro-2H-chromene was synthesized analogously to Example33b) from 4-chloro-1-fluoro-2-(2-propynyloxy)benzene (4.6 g, 25 mmol) togive 1 g of product (purified by column chromratography on alumina,ethyl acetate/n-hexane 1:15) as colourless oil. Yield 22%.

d) ethyl+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate

Ethyl+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylatewas synthesized analogously to Example 33c from5-chloro-8-fluoro-2H-chromene (1 g, 5.4 mmol) to give 360 mg of +/−cisproduct (purified by column chromatography on silica, ethylacetate/n-hexane 1:20) as white solid. Yield 25%.

e)+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid

+/−cis-7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 33d from ethyl+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate(360 mg, 1.3 mmol) to give 259 mg of +/−cis acid (80%).

EXAMPLE 60 N-[(1S,1aR,7bR) or(1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzothiopyran-1-yl]-N′-(5-cyano-2-pyridinyl)ureaa) 3,4-dihydro-2H-1-benzothiopyran-4-ol

A solution of thiochroman-4-one (9 g) in ether (27 ml) was added slowlyto a mixture of lithium aluminium hydride (0.53 g) in ether (54 ml).After the end of the addition, the mixture was refluxed for 2 hours. Thereaction mixture was cooled and ice was added, followed by water and bya solution of 20% H₂SO₄. The water phase was washed twice with ether.The ether phase was washed twice with NaOH 2N, and once with water,dried over MgSO₄ and evaporated. The clear oil (8.9 g) crystallisedafter few hours. Rdt=97%

b) 2H-1-benzothiopyran and 4H-1-benzothiopyran

4-Thiochromanol (8.9 g) and potassium acid sulfate (0.89 g) were placedin a flask and evacuated to 1 mm. The-flask was put in a bath-heated at90° C. until the alcohol melted. The magnetic stirrer was started andthe bath slowly brought to 120° C. Dehydration was rapid and a mixtureof the product and water distilled and was collected in a ice-cooledreceiver. The product was taken up in ether and dried. The crude product(7 g, Rdt=88%) wasn't purified. The NMR showed the presence of 10% ofthe 4H-1-benzothiopyran.

c) Ethyl ester1,1a,2,7b-tetrahydro-cyclopropa[c][1]benzothiopyran-1-carboxylic acid,(1S,1aR,7bR) or (1R,1aS,7bS)

Ethyl diazoacetate was added slowly to 500 mg of thiochromene at 140 C.The reaction was followed by Gas chromatography and stopped when allstarting material was consumed (about 7 hours). The residue was purifiedby flash chromatography (5% ether in hexane). The cis isomer (46,5 mg,Rdt=6%) was identified by NMR spectroscopy.

d) 1,1a,2,7b, tetrahydro-cyclopropa[c][1]benzothiopyran-1-carboxylicacid, (1S, 1aR,7bR) or (1R,1aS,7bS)

A mixture of the cis isomer (46,5 mg), LiOH (4 eq., 19 mg) in 5 ml ofmethanol/25% H₂O was refluxed for 1 hour. After evaporation of thesolvent under vacuum, the residue was dissolved in water and washed withether. The water phase was acidified with concentrated HCl, andextracted twice with dichloromethane. After drying, the organic phasewas evaporated and gave the desired acid (30 mg). Rdt=73%.

EXAMPLE 61(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid a) (2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol

Solution of BuLi (2.5M) in hexane (9.6 ml; 0.024 mol) was added to astirred solution of 2,5-difluoroanisol (2.88 g, 0.02 mol) in dry THF (30ml) at −70 C, followed after 2 h by solution of zinc chloride (3.6 g;0.026 mol) in dry THF (50 ml). The reaction temperature was allowed toraise to room temperature and then stirring was maintained at roomtemperature for 30 min. Pd(OAc)₂ (8 mg; 0.2 mol %) was added, followedby ethyl cis-3-bromoacrylate (3.58 g; 0.02 mol). The reaction mixturewas placed in preheated oil bath and heated under reflux for 1 h. Theresulting reaction mixture was chilled to −78 C and 60 ml (0.06 mol) ofDIBAL (1M solution in hexanes) was added dropwise. The stirring wascontinued at −78 C for 2 h and 1 h at room temperature. The reaction wasquenched with water and all solids were dissolved by addition of HCl.The organic phase was diluted with ether, separated, washed with 5N HCl,brine and evaporated in vacuo. The residue was Kugelrohr distilled(1.5×10⁻² mbar, 150 C) to give 3.7 g (92%) of crude(2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol, which contains ˜6%of other regioisomers. The crude product was used in the next stepwithout further purification.

¹H-NMR (CDCl₃): 7.00 (m, 1H); 6.77 (m, 1H); 6.31 (app. d, 1H); 6.12(app. dt, 1H); 4.08 (br. t, 2H); 3.89 (d, 3H); 1.80 (br. t, 1H).

b) (2Z)-3-(3,6-difluoro-2-methoxyphenyl)prop-2-enyl diazoacetate

The p-toluenesulfonylhydrozone of glyoxylic acid chloride (5.16 g; 0.02mol) was added to a solution of(2Z-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol (3.6 g; 0.018 mol) indry CH₂Cl₂ (50 ml) at −5 C, and N,N-dimethylaniline (2.5 ml; 0.02 mol)was added slowly. After stirring for 30 min at −5 C, Et₃N (12 ml; 0.09mol) was added slowly. The resulting mixture was stirred for 15 min at−5 C and then for 30 min at room temperature, whereupon water (˜50 ml)was added. The organic phase was separated washed with water, brine andconcentrated in vacuo. Flash chromatography (silica, EA:Hex; 1:1.5) gave3.86 g (80%) of product as a yellow solid.

¹H-NMR (CDCl₃): 7.00 (m, 1H); 6.76 (m, 1H); 6.41 (app. d, J=12.2 Hz;1H); 6.00 (app. dt, J=12.2; 6.10 Hz; 1H); 4.71 (br. s, 1H); 4.67 (dt,2H); 3.89 (d, 3H).

c)(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one

(2Z)-3-(3,6-difluoro-2-methoxyphenyl)prop-2-enyl diazoacetate (3.45 g,0.013 mol) was dissolved in 100 ml of dried degassed dichloromethane andadded dropwise to the solution of chiral Doyle catalyst (Aldrich, alsoavailable from Johnsson Matthey, 10 mg, 0.1 mol %) in 50 ml ofdichloromethane under argon at ambient temperature over a period of ˜6h. The initial blue color had turned to olive by the end of theaddition. The reaction mixture was concentrated in vacuo and the crudeproduct was purified by flash chromatography (silica, EA:Hex, 1:5→1:1)to give 2.72 g (88%) of(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-oneas colorless solid. Enantiomeric purity could be checked on this stageusing Chiracel OD column, 10% IPA in hexane—94% ee.

¹H-NMR (CDCl₃): 7.00 (m, 1H); 6.72 (m, 1H); 4.33 (dd, 1H); 4.10 (d, 1H);402 (d, 3H); 2.66 (m, 2H); 2.37 (t, 1H).

d) (1S,1aR,7bS)-1-(bromomethyl)-4,7-difluoro-1a,7b-dihydrocyclopropa[c]chromene-2(1H)-one

(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one(130 mg, 0.55 mmol) was mixed with 1.2 ml of 30% HBr/AcOH (6 mmol) andheated in a sealed vessel at stirring for about 4 h at 90° C. Thereaction mixture was then cooled down, mixed with water and extractedinto diethyl ether (3×20 ml). Ether extract was washed with sat sodiumbicarbonate solution and brine. Dried over magnesium sulfate.Concentration gave 160 mg of white solid material. 98% yield.

¹H-NMR (CDCl₃): 7.08 (m, 1H); 6.88 (m, 1H); 3.44 (dd, 1H); 3.06 (t, 1H);2.96 (dd, 1H); 2.64 (dd, 1H); 2.46 (m, 1H).

e)(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid

(1S,1aR,7bS)-1-(bromomethyl)-4,7-difluoro-1a,7b-dihydrocyclpropa[c]chromen-2(1H)-one(360 mg, 1.2 mmol) was mixed with the solution of NaOH (0.1 g, 2.5 mmol)in 5 ml of water and heated at stirring for 1 h at 90° C. Aftercompletion the reaction mixture was cooled down and extracted intodiethyl ether (2×20 ml). Water phase was acidified with conc. HCl. Theprecipitate formed was collected by filtration to give 180 mg of pureproduct. Mother liquor was extracted into ether and washed with brine,dried over magnesium sulfate. Concentration gave additional 70 mg ofproduct (containing up to 15% of impurities). Overall yield about 92%.

¹H-NMR (CDCl₃); 6.86 (m, 1H); 6.54 (m, 1H); 4.48 (m, 2H); 2.62 (t, 1H);2.20 (t, 1H); 2.11 (m, 1H).

EXAMPLE 62 a) cis ethyl ester1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thiophene-1-carboxylic acid,(1S,1aS,6bR) or (1R,1aR,6bS)

Ethyl diazoacetate is added slowly to 10 g of thiophene at 140° C. Thereaction was checked by gas chromatography and stopped after 7 hours.The residue is purified by flash chromatography (5% ether in hexane).The cis isomer (917 mg, Rdt=6%) was identified by NMR spectroscopy.

REFERENCE

-   Badger G. M. et al, J. Chem. Soc., 1958, 1179-1184.-   Badger G. M. et al, J. Chem. Soc., 1958, 4777-4779.

b) cis 1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thiophene-1-carboxylicacid, (1S,1aS,6bR) or (1R,1aR,6bS)

A mixture of the cis isomer (443 mg), LiOH (193 mg) in 15 ml ofmethanol/25% H₂O is refluxed for 1 hour. After evaporation of thesolvent under vacuum, the residue is dissolved in water and washed withether. The water phase is acidified with concentrated HCl, and extractedtwice with dichloromethane. After drying, the organic phase isevaporated and gave the desired acid (313.6 mg). Rdt=81%.

EXAMPLE 63(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-2-methoxy-3-oxabicyclo[3.1.0]hexane

a) Iodo-3-oxabicyclo[3.1.0]hexan-2-one

The title compound is synthesised in the depicted stereochemistry asdescribed in Doyle J Amer Chem Soc 117 (21) 5763-5775 (1993)

b) Iodo-2-methoxy-3-oxabicyclo[3,1,0]hexane

The title compound is synthesised in the depicted stereochemistry asdescribed in Martin et al Tett Lett 39 1521-1524 (1998).

c)(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-2-methoxy-3-oxabicyclo[3.1.0]hexane

2,4-diflouroanisol (90 mg, 0.62 mmol) was dissolved in anhydrous,degassed, THF (7 ml) and cooled to −78° C. under N₂. nBuLi, 2,5 M inhexane, (0.30 ml, 0.77 mmol) was added and the reaction mixture wasstirred at −78° C. for 2 hrs. ZnCl₂ (150 mg, 1.1 mmol), as a solution inanhydrous THF (7 ml), was added and the reaction mixture was allowed towarm to ambient temperature for 2 hrs. Iodo-2-methoxy-3-oxabicyclohexane(150 mg, 0.63 mmol), Pd (OAc)₂ (1.5 mg, 6.2 mol), and ligandTris(2,4-di-tert-butylphenyl)phosphite (40 mg, 62 μmol) were mixed inanhydrous THF (7 ml) and added to the reaction mixture. The reactionmixture was heated at reflux for 3 days and quenched with H₂O. Diethylether was added and the layers were separated, the organic layer waswashed with H₂O and aq. sat. NaCl, dried over MgSO₄, filtered andconcentrated to give the title compound, otherwise denoted2,4-di-fluoro-5-(cyclopropylacetal)anisol. Column chromatography onsilica (EtOAc/Hexane 1:3) gave (4) 50 mg, 31%.

¹H NMR (CDCl₃) δ (ppm): 6.88-6.94 (m, 1H, ArH), 6.68-6.73 (m, 1 H, ArH),4.82 (s, 1H, CHOCH₃), 3.97-3.98 (m, 1H, CHOCH), 3.94 (s, 3H, OCH₃),3.79-3.81 (m, 1H, CHOCH), 3.30 (s, 3H, OCH₃), 2.13-2.19 (m, 2H, 2xCH-cyclopropyl), 1.89 (tr, J=7.81 Hz, 1H, CH cyclopropyl).

EXAMPLE 64cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

BBr₃ 1M solution in CH₂Cl₂ (5.8 ml; 5.8 mmol 2.1 eq) was added tostarting lactone,(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-onefrom example 42c) (0.66 g; 2.75 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h. Acetonitrile (5.8 ml) was added and stirringwas continued for 3 h at 0° C. The reaction mixture was quenched byaddition of water and the organic phase was separated. Water phase wasextracted with CH₂Cl₂ and combined organic phases were evaporated. NaOH(0.33 g; 8.25 mmol; 3 eq) in water (˜5 ml) was added to the resultedresidue and stirred at 80° C. for 45 min. The reaction mixture wasextracted with ether to remove none acidic impurities. The residualether in water phase was evaporated in vacuo and conc. HCl was added topH of ˜3. After ˜1 h the solid was filtered off yielding 0.497 g (80%)of crude final acid as brownish solid. The crude acid was dissolved in 6ml of EtOH/H₂O (40/60 v/v) and treated with activated carbon. The hotsolution was filtered and left for crystallization. Yield 0.4 g (64%).

¹H-NMR (CDCl₃): 10.32 (br s, ˜1H), 7.68 (d, 2H), 7.37 (s, 1H), 7.32 (d,2H), 6.96 (s, 1H), 6.87 (m, 1H), 6.62 (dt, 1H), 4.44 (dd, 1H), 4.33 (dd,1H), 3.53 (m, 1H), 2.56 (m, ˜1H), 1,96 (m, 1H). LC-MS: M⁺434.

EXAMPLE 65 a) 1,1a,66a-tetrahydrocyclopropa[a]indene-1-carboxylic acidethyl ester

Indene is diluted in 100 ml dichloroethane. Around 10 mg of CuI andaround 10 mg Pd(OAc)₂ is added. 25 ml of the resultant mixture isdropwise added to 25 ml ethyldiazoacetate and refluxed for 30 minutes.The solution is filtered through Al₂O₃ which is eluted with aEtOAC/hexane gradient. The eluate is evaporated vigorously at 100°, 2mmHg to yield the title compound (36 g).

b) 1,1a,66a-tetrahydrocyclopropa[a]indene-1-amine

The product of step a) is boiled with around 50 g NaOH in 200 ml10:1MeOH:H₂O for 2 hours. The mixture is diluted with water, washed withdichloroethane, evaporated with HOAc, extracted with dichloroethane,washed with water, dried with sulphate, filtered and evaporated to yield25 g of the acid, 95% pure. DPPA 275.2 δ=1.128 10 ml, 46.5 mmol TEA 7.1ml 1.1ee and 7.3 g of the acid (mass 174.12, 0.9ee) is mixed in 200 mltoluene and refluxed for around 2 hours. The product is evaporated anddissolved in dioxane 200 ml. 25 ml HCl(aq) and 25 ml water is added andthe mixture agitated for 60 minutes at room temperature. The solution ispartioned with acid/base in water/dichloroethiane. The organic, phase isdired, filtered and evaporated. The product is chromatographed through asilica 60 column to yield 660 mg of 85% pure cis amine, mol wt 145.11.

EXAMPLE 66±cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,6,6a-tetrahydro-cyclopropa[a]inden-1-yl)-ureaa) ±cis-1,1a,6,6a-Tetrahydro-cyclopropa[a]indene-1-carboxylic acid ethylester

To a mixture of indene (11.6 g, 100 mmol) and Cu₂Br₂ (0.10 g, 0.35 mmol)in 1,2-dichloroethane

(200 mL) at 80° C., was added dropwise (3 h) a solution of ethyldiazoacetate (17.1 g, 150 mmol) in 1,2-dichloroethane (35 mL). After 15min at 80° C., the reaction mixture was washed with H₂O (200 mL). TheH₂O phase was washed with CH₂Cl₂ (50 mL) and the solvent of the combinedorganic phases was removed under reduced pressure. The crude product wascolumn chromatographed (silica gel, 5→10% EtOAc in Hexane), to give 3.63g (18%) of ±cis-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylicacid ethyl ester and 6.68 g (33%) of±trans-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic acid ethylester as a byproduct.

¹H-NMR (CDCl₃): 7.30-7.05 (m, 4H), 3.81 (q, 2H), 3.36 (d, 1H), 3.18 (dd,1H), 2.92 (m, 1H), 2.24 (m, 1H), 1.99 (dd, 1H), 0.92 (t, 3H).

b) ±cis-1,1a,6,6a-Tetrahydro-cyclopropa[a]indene-1-carboxylic acid

±cis-1,1a,6,6a-Tetrahydro-cyclopropa[a]indene-1-carboxylic acid wassynthesized from±cis-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic acid ethylester (3.53 g, 15.5 mmol), LiOH (539 mg, 22.5 mmol), H₂O (10 mL) andMeOH (20 mL) which were heated to reflux for 2 h, concentrated andacidified to precipitate 1.62 g (62%) of±cis-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic acid as awhite solid. The product was not crystallized.

¹H-NMR (CDCl₃): 10.95 (br s, 1H, 7.35-7.02 (m, 4H), 3.29 (d, 1H), 3.14(dd, 1H), 2.96 (m, 1H), 2.27 (m, 1H), 1.91 (dd, 1H).

The reaction mixture was concentrated under reduced pressure, benzene(20 mL) was added and the reaction mixture was washed with 1N HCl (30mL), H₂O (30 mL) and brine (30 mL). The solvent of the organic phaseswas removed under reduced pressure. The crude product was columnchromatographed (silica gel, 4→5% MeOH in CH₂Cl₂), to give 25 mg (5%) of±cis-1-(5-cyano-pyridin-2-yl)-3-(1,1a,6,6a-tetrahydro-cyclopropa[a]inden-1-yl)-urea.

¹H-NMR (DMSO-d₆): 9.58 (s, 1H), 8.18 (d, 1H), 7.96 (dd, 1H), 7.40-7.25(m, 3H), 7.17-7.05 (m, 3H), 3.27-3.13 (m, 2H), 2.80-2.73 (m, 2H), 2.05(dd, 1H).

EXAMPLE 67±cis-1-(5-Cyano-pyridin-2-yl)-3-(1a,2,3,7b-tetrahydro-cyclopropa[a]naphthalen-1-yl)-ureaa) 1a,2,3,7b-Tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acidethyl ester1a,2,3,7b-Tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid ethylester was

Synthesized analogously to Example 66 from 1,2-dihydronaphthalene (3.91g, 30 mmol), to give 688 mg (11%) of1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid ethylester (a 56/39 mixture of cis and trans isomers).

¹H-NMR (CDCl₃): 7.35-6.95 (m, 4H), 4.30-3.85 (m, 2H), 2.90-1.00 (m,10H).

b) 1a,2,3,7b-Tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid

1a,2,3,7b-Tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid wassynthesized analogously to Example 66b from1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid ethylester (688 mg, 3.18 mmol, a 56/39 mixture of cis and trans isomers), togive 540 mg (90%) of1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid (a56/39 mixture of cis and trans isomers). The product was notcrystallized.

¹H-NMR (CDCl₃): 11.36 (br s, 1H), 7.30-6.95 (m, 4H), 2.80-1.65 (m, 7H).

EXAMPLE 68 a)1,1a,2,3,4,8b-Hexahydro-benzo[a]cyclopropa[c]cycloheptene-1-carboxylicacid ethyl ester

1,1a,2,3,4,8b-Hexahydro-benzo[a]cyclopropa[c]cycloheptene-1-carboxylicacid ethyl ester was synthesized analogously to Example 66a from6,7-dihydro-5H-benzocycloheptane (4.40 g, 30.5 mmol), to give 3.43 g(49%) of1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropa[c]cycloheptene-1-carboxylicacid ethyl ester (a 1/10 mixture of cis and trans isomers).

¹H-NMR (CDCl₃): 7.40-6.90 (m, 4H), 4.30-4.00 (m, 2H), 3.30-0.50 (m,12H).

b)1,1a,2,3,4,8b-Hexahydro-benzo[a]cyclopropa[c]cycloheptene-1-carboxylicacid

1,1a,2,3,4,8b-Hexahydro-benzo[a]cyclopropa[c]cycloheptene-1-carboxylicacid was

synthesized analogously to Example 66 from1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropa[c]cycloheptene-1-carboxylicacid ethyl ester (3.43 g, 14.9 mmol, a 1/10 mixture of cis and transisomers), to give 2.81 g (93%) of1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropa[c]cycloheptene-1-carboxylicacid (a 1/10 mixture of cis and trans isomers). The product was notcrystallized.

¹H-NMR (CDCl₃): 10.76 (br s, 1H), 7.40-7.00 (m, 4H), 3.30-0.50 (m, 9H).

EXAMPLE 69 a) 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol

6-Methoxytetralone (10 g, 0.057 mol) was mixed with 150 ml of dryethanol and sodium borohydride (1.2 eq) was added by portions to thestirred mixture. The reaction mixture was left to stir at ambienttemperature for 15 h. The reaction mixture was then concentrated byrotary evaporation, mixed with 100 ml of water and heated for 1 h at 45°C. The resulting mixture was extracted into diethyl ether (3×80 ml).Combined organic extract was dried over Na₂SO₄ and concentrated byrotary evaporation to give 10.39 g of yellow oil which was used in thenext step without additional purification.

b) 7-methoxy-1,2-dihydronaphthalene

Crude 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (10.3 g, 0.058 mol)was dissolved in 100 ml of toluene and heated in an oil bath (115° C.).P-tolylsulphonic acid (20 mg) was added to the reaction mixture and itwas refluxed for about 1 h. The reaction was monitored by GC. Thereaction mixture was then cooled and washed with sat. NaHCO₃ solution,water and brine and organic layer was dried over Na₂SO₄. Concentrationgave 8.87 g of light brown oil. Yield 96%.

c) Ethyl5-methoxy-1a,2,3,7b-tetrahydro-1H-yclopropa[a]aphthalene-1-carboxylate

7-Methoxy-1,2-dihydronaphthalene (8.8 g, 0.055 mol) was mixed with 10 mlof degassed absolute methylene chloride and 20 mg of rhodium acetate(appr. 0.1 mol %. The reaction mixture was bubbled with nitrogen andethyl diazoacetate (2 eq, 50% solution in degassed abs. methylenechloride) was added slowly through the syringe (flow rate about 1ml/hour) to the stirred solution at ambient temperature. Gas evolutionstarted upon the addition. The reaction was monitored by GC. Additionalamount of catalyst was added during the reaction (about 20 mg). GC-ratioof cis/trans isomers was 21:48.

After the reaction was complete according to GC data the reactionmixture was washed with saturated NH₄Cl solution and brine. Themethylene chloride solution was dried over Na₂SO₄. Concentration gave 13g of crude product as yellow oil. Purified by column chromatography onsilica (200 g, ethyl acetate/hexane 1:20). Only trans isomer wasobtained in pure form. The required cis form could not be purified bythe technique used. Fractions which were more enriched with requiredproduct were combined (200 mg, cis/trans ratio 70:30 according to GC)and used for further transformations.

d)5-Methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid

Ethyl5-methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate(0.2 g, 0.8 mmol) was dissolved in 2 ml of methanol and the solution ofsodium hydroxide (0.2 g, 50 mmol) in 2 ml of water was added to thereaction mixture and stirred at ambient temperature overnight. Theextraction of basic reaction mixture into hexane showed that no startingmaterial present. The reaction mixture was acidified with excess of 3MHCl solution (pH=1), and extracted into ethylacetate (3×15 ml). Thecombined extracts were washed with water and brine, dried over Na₂SO₄and concentrated by rotary evaporation to give 0.1 5 g of mixture ofcis/trans acids as white solid.

EXAMPLE 70 a) 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol

7-Methoxy-3,4-dihydro-1(2H)-naphthalenol was synthesized analogously toExample 69a from 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenone (5 g, 28mmol), to give about 5 g of crude product (quantitative yield), whichwas used in the next step without additional purification.

b) 6-methoxy-1,2-dihydronaphthalene

6-Methoxy-1,2-dihydronaphthalene was synthesized analogously to Example69b from 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol to give 4.4 g ofproduct as brown yellow oil (96% yield from7-methoxy-1,2,3,4-tetrahydro-1-naphthalenone).

c) ethyl6-methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate

Ethyl6-methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylatewas synthesized analogously to Example 67 from6-methoxy-1,2-dihydronaphthalene (4.4 g, 28 mmol) at addition rate 0.7ml/h to give 9.68 g of crude product as orange-brown oil. Purified bycolumn chromatography on silica (200 g, ethylacetate/hexane 1:10). Threefractions were collected: fraction enriched with cis isomer (75% byGC)—0.16 g, mixed fraction—1.76 g, and fraction contained pure transisomer—1 g. Total yield 45%.

d)6-methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid

6-Methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid was synthesized analogously to Example 69d) from ethyl6-methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate(0.16 g, 0.65 mmol) to give 0.1 g of product as white crystals. Yield71%.

EXAMPLE 71 a) 7,8-dihydro-2-naphthalenol

7-Methoxy-1,2-dihydronaphthalene (6.4 g, 40 mmol) was dissolved in abs.DMF and bubbled with argon sodium ethylthiolate (2.5 eq) was added andthe reaction mixture was heated at stirring at 160° C. for about 4 h.Reaction was monitored by GC. Reaction mixture was diluted with water,acidified with 3M HCl and extracted into ethylacetate. Organic extractwas washed with water and brine, dried over Na₂SO₄ and concentrated byrotary evaporation. Purification by column chromatography on silica (200g, ethylacetate/hexane) gave 5.36 g of desired phenol. Yield 92%.

b) 7,8-dihydro-2-naphthalenyl trifluoromethanesulfonate

7,8-Dihydro-2-naphthalenol (5.3 g, 37 mmol) was mixed with triethylamine(6.2 ml, 44 mmol) in abs. methylenechrloride and cooled under nitrogenin the ice/brine bath. Triflic anhydride (7.4 ml, 44 mmol) was added tothe stirred solution through syringe during 10 min. The temperature wasallowed to rise slowly up to room temperature. The reaction mixture wasthen washed with water and brine and dried over Na₂SO₄. The crudeproduct was purified by column chromatography on silica. 9 g of brownliquid was obtained. Yield 88%.

c) Ethyl5-{[(trifluoromethyl)sulfony]oxy}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate

Ethyl5-{[(trifluoromethyl)sulfonyl]oxy}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylatewas synthesized analogously to Example 5c from7,8-dihydro-2-naphthalenyl trifluoromethanesulfonate (9 g, 32 mmol) ataddition rate 1 ml/h to give 13 g of crude product as orange-brown oil.Purified by column chromatography on silica (200 g, ethylacetate/hexane1:15). Fraction enriched with cis isomer (80% by GC)—0.64 g wascollected and used for futher transformations.

d) Ethyl5-cyano-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate

Ethyl5-{[(trifluoromethyl)sulfonyl]oxy}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate(0.2 g, 0.5 mmol) was mixed with Zn(CN)₂ (0.82 mmol) and Pd(Ph₃P)₄ (56mg, 10 mol %) in DMF (4 ml), bubbled with argon for 5 min and heated atstirring in a closed vial for 14 h at 100° C. Reaction was monitored byGC. The reaction mixture was concentrated by rotary evaporation, mixedwith saturated NH₄Cl and extracted into ethylacetate (3×15 ml). Organicextract was washed with water and brine, dried under Na₂SO₄.Concentration gave 0.12 g of product as an oil (yield 90%).

d) 5-cyano-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid

5-Cyano-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid was synthesized analogously to Example 69d from ethyl5-cyano-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate(0.12 g, 0.5 mmol) to give 0.1 g of product as white crystals. Yield94%.

¹H-NMR (DMSO-d₆): 9.70 (br s, 1H), 8.32 (br s, 1H), 8.03 (dd, 1H),7.46-7.63 (m, 4H), 7.32 (br s, 1H), 3.18-3.10 (m, 2H), 2.76-2.65 (m 1H),2.62-2.51 (m, 1H), 2.34 (t, 1H), 2.01-1.80 (br m, 2H), 1.78-1.69 (br m,1H).

EXAMPLE 71A a) Ethyl5-[(trimethylsilyl)ethynyl]-1,1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate

Ethyl5-{[(trifluoromethyl)sulfonyl]oxy}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate(0.2 g, 0.5 mmol) was mixed with trimethylsylilacetylene (0.2 ml, 1.37mmol), DPP (35 mg, 10 mol %), Pd(dba)₂ (30 mg, 10 mol %) and CuI (3 mg)in Et₃N (2.5 ml), bubbled with argon for 5 min and heated at stirring ina closed vial for 14 h at 95° C. Reaction was monitored by GC. Thereaction mixture was concentrated by rotary evaporation, mixed withsaturated NH₄Cl and extracted into ethylacetate (3×15 ml). Organicextract was washed with water and brine, dried under Na₂SO₄.Concentration gave 0.15 g of product as an oil (yield 87%).

b)5-Ethynyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid

Ethyl5-[(trimethylsilyl)ethynyl]-1a,2,3,7b-tetrahydro-1-H-cyclopropa[a]naphthalene-1-carboxylate(0.2 g, 0.64 mmol) was dissolved in 4 ml of methanol and the solution ofsodium hydroxide (0.05 g, 1.2 mmol) in 2 ml of water was added to thereaction mixture and stirred at heating at 65° C. for 6 h. Theextraction of basic reaction mixture into hexane showed that no startingmaterial present. The reaction mixture was acidified with excess of 3MHCl solution (pH=1), and extracted into ethylacetate (3×15 ml). Thecombined extracts were washed with water and brine, dried over Na₂SO₄and concentrated by rotary evaporation to give 0.12 g of mixture ofcis/trans acids (85:15) as white solid. Yield 88%. 7

EXAMPLE 72 a) 5,8-difluoro-4-methyl-3,4-dihydro-1(2H)-naphthalenone

1,4-Difluorobenzene (22 ml, 210 mmol) was mixed with gamma-valerolactone(4 ml, 42 mmol) and AlCl₃ (28 g, 210 mmol) was added by portions to thestirred reaction mixture. The reaction mixture was then refluxed atstirring for 16 h (oil bath 110° C.). The reaction mixture was cooleddown (ice/brine bath) and ice/conc. HCl was added and stirred untilhomogeneous mixture was obtained. The reaction mixture was thenextracted into methylene chloride, washed with water (4×10 ml) andsodium bicarbonate solution (3×100 ml). The organic extract was driedover Na₂SO₄. Concentration by rotary evaporation gave 6.7 g of productas yellow powder. Yield 81%.

b) 5,8-difluoro-4-methyl-1,2,3,4-tetrahydro-1-naphthalenol

5,8-Difluoro-4-methyl-1,2,3,4-tetrahydro-1-naphthalenol was synthesizedanalogously to Example 69a from5,8-difluoro-4-methyl-3,4-dihydro-1(2H-naphthalenone to give 1.8 g ofcrude product, which was used in the next step without additionalpurification.

c) 5,8-difluoro-1-methyl-1,2-dihydronaphthalene

5,8-Difluoro-1-methyl-1,2-dihydronaphthalene was synthesized analogouslyto Example 69b from5,8-difluoro-4-methyl-1,2,3,4-tetrahydro-1-naphthalenol (1.8 g, 9.1mmol) to give 1.5 g of product as brown yellow oil (90% yield from5,8-difluoro-4-methyl-1,2,3,4-tetrahydro-1-naphthalenone).

d) Ethyl4,7-difluoro-3-methyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxcylate

Ethyl4,7-difluoro-3-methyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylatewas synthesized analogously to Example 69c from5,8-difluoro-1-methyl-1,2-dihydronaphthalene (3.5 g, 19 mmol) ataddition rate 0.5 ml/h to give crude product as yellow-brown oil.Purified by column chromatography on silica (200 g, ethylacetate/hexane1:15) to give 5.2 g of the mixture of diastereomeric esters togetherwith dimers of EDA as coloureless oil (GC ratio: anti-45%; 40%/trans:cis/, syn-11%; 2.3% /trans:cis).

e)+/−anti-cis-4,7-difluoro-3-methyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid

Ethyl4,7-difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate(5.25 g, 20 mmol, ˜50:50 mixture of cis and trans isomers) was dissolvedin 2.5 ml of methanol and the solution of sodium hydroxide (0.4 g, 10mmol) in 2.5 ml of water was added to the reaction mixture and stirredat ambient temperature overnight. The reaction mixture was extractedinto hexane (3×30 ml). The combined extracts were washed with water andbrine, dried over Na₂SO₄ and concentrated by rotary evaporation to give1.12 g of cis esters as colourless oil (mixture of ethyl and methylesters—94% according to GC). The mixture obtained was dissolved in 1.5ml of methanol and the solution of sodium hydroxide (0.2 g, 5 mmol) in1.5 ml of water was added to the reaction mixture and stirred at 95° C.for 40 min. The reaction mixture was acidified with excess of 3M HClsolution (pH=1), and extracted into ethylacetate (3×15 ml). The combinedextracts were washed with water and brine, dried over Na₂SO₄ andconcentrated by rotary evaporation to give 0.93 g anti-+/−cis acid asslightly orange crystals. Yield 20% (appr. quantitative if calculatedfor starting cis isomer).

EXAMPLE 73 a) 4,7-difluoro-3-methyl-1-indanone

4,7-Difluoro-3-methyl-1-indanone was synthesized analogously to Example72a from beta-butyrolactone (4 ml, 52 mmol) to give 7.19 g of yellowpowder (85:15 mixture of corresponding indanone and tertralone accordingto GC). The product was purified by column chromatography on silica (200g, ethylacetate/hexane) to give 3.7 g (40% yield) of pure producttogether with mixed fraction and fraction containing pure tetralone.

b) 4,7-difluoro-3-methyl-1-indanol

4,7-Difluoro-3-methyl-1-indanol was synthesized analogously to Example69 from 4,7-difluoro-3-methyl-1-indanone (3.7 g, 20 mmol), to give about3.75 g of crude product (quantitative yield), which was used in the nextstep without additional purification.

c) 4,7-Difluoro-1-methyl-1H-indene

4,7-Difluoro-1-methyl-1H-indene was synthesized analogously to Example66 from 4,7-difluoro-3-methyl-1-indanol (3.75 g, 9.1 mmol) to give 2.36g of product as beige liquid (70% yield).

d) Ethyl2,5-difluoro-6-methyl-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate

Ethyl2,5-difluoro-6-methyl-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylatewas synthesized analogously to Example 69c from4,7-difluoro-1-methyl-1H-indene (1.32 g, 7.9 mmol) at addition rate 0.4min to give crude product as yellow-brown oil. Purified by columnchromatography on silica (100 g, ethylacetate/hexane 1:15) to give 0.61g of the mixture of diastereomeric esters cis- and trans-esters ascoloureless oil (cis/trans ratio: 84:16 according to NMR). Yield 30%.

e)anti-+/−cis-2,5-difluoro-6-methyl-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid

anti-+/−cis-2,5-Difluoro-6-methyl-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid was synthesized analogously to Example 34 from ethyl2,5-difluoro-6-methyl-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate(0.61 g, 2.4 mmol) by stepwise hydrolysis first with 20 mol. % of NaOHand then with the excess of NaOH at heating to give 380 mg of product aswhite crystals. Yield 70% (appr. quantitative if calculated for startingcis isomer).

EXAMPLE 74 a) 5,8-difluoro-3,4-dihydro-1(2H)-naphthalenone

5,8-Difluoro-3,4-dihydro-1(2H)-naphthalenone was synthesized togetherwith 4,7-difluoro-3-methyl-1-indanone according to procedure describedin Example 73a. Separated by column chromatography on silica. 0.77 g ofpure product was obtained yield 8%.

b) 5,8-difluoro-1,2,3,4-tetrahydro-1-naphthalenol

5,8-Difluoro-1,2,3,4-tetrahydro-1-naphthalenol was synthesizedanalogously to Example 69a from5,8-difluoro-3,4-dihydro-1(2H)-naphthalenone (0.77 g, 4.2 mmol), to givecrude product (quantitative yield), which was used in the next stepwithout additional purification.

c) 5,8-difluoro-1,2-dihydronaphthalene

5,8-Difluoro-1,2-dihydronaphthalene was synthesized analogously toExample 69b from 5,8-difluoro-1,2,3,4-tetrahydro-1-naphthalenol to give0.67 g of crude product as brownish liquid (90% yield from5,8-difluoro-3,4-dihydro-1(2H)-naphthalenone).

Additional amount of product was also obtained from the mixture of5,8-difluoro-3,4-dihydro-1(2H)-naphthalenone and4,7-difluoro-3-methyl-1-indanone by reduction followed by dehydration.The mixture of corresponding indene and naphthalene is easy to separateby column chromatography on silica (ethyl acetate/hexane 1:20).

d) ethyl4,7-difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate

Ethyl4,7-difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylatewas synthesized analogously to Example 69c from5,8-difluoro-1,2-dihydronapthalene (0.7 g, 4.2 mmol) at addition rate0.4 ml/h to give crude product as yellow-brown oil. Purified by columnchromatography on silica (100 g, ethylacetate/hexane 1:15) to give 0.45g of the mixture of cis- and trans-esters as coloureless oil (cis/transratio: 33:67 according to GC)4,7-difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid

e)4,7-Difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid

4,7-Difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylicacid was synthesized analogously to Example 72e from ethyl4,7-difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate(0.45 g, 1.8 mmol) by stepwise hydrolysis first with excess of NaOH atr.t. and then with the excess of NaOH at heating (60° C., 1.5 h) to give80 mg of product as white crystals (cis/trans ratio 78:22 according toHPLC).

EXAMPLE 75 a) 6-Bromoindene

This compound was prepared analogously to Examples 69a & 69b from5-bromo-1-indanone (4.0 g, 18.8 mmol) to give 2.4 g (65%) of6-bromoindene.

b) (±)-cis-Ethyl4-bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate

This compound was prepared analogously to Example 69c from 6-bromoindene(1.95 g, 10 mmol). Purification on silica gel starting with hexanesfollowed by hexanes with 2% diethyl ether and finally hexanes with 5%diethyl ether afforded 670 mg (24%) of the cis-ester.

c) (±)-cis-4-Bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid

This acid was synthesized analogously to Example 69d starting with 330mg (1.77 mmol) of the compound from Example 75b to give 232 mg (79%) of(±)-cis-4-Bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid.

EXAMPLE 76 a) (±)-cis-Ethyl4-cyano-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate

This compound was prepared analogously to Example 71d from (±)-cis-ethyl4-bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate (200 mg,0.7 mmol) to give, after purification on silica gel using hexanes with10% ethyl acetate as the eluent, 73 mg (46%) of (±)-cis-ethyl4-cyano-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate.

b) (±)-cis-4-Cyano-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid

This acid was synthesized analogously to Example 69d starting with 73 mg(0.32 mmol) of the compound from Example 76a to give 59 mg (95%) of(±)-cis-4-cyano-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid.

EXAMPLE 77 a) 4,7-Difluoro-1-indanone

2,5-Difluorocinnamic acid (5.0 g, 27.2 mmol) was dissolved in 25 ml ofethanol and a catalytic amount of 10% Pd on carbon was added. Thereaction mixture was hydrogenated at normal pressure for a period of 3hrs. Filtration through celite and evaporation of the solvent affordedcrude 3-(2,5-difluorophenyl)-propionic acid. This acid was dissolved in75 ml of toluene and 5 ml of thionyl chloride was added. The reactionmixture was heated at +110° C. for a period of 2 hrs. Evaporation of thesolvent afforded crude 3-(2,5-difluorophenyl)-propionyl chloride, whichwas dissolved in 25 ml of carbon disulfide and added drop wise to asuspension of 4 g of aluminium chloride in 100 ml of carbon disulfide.The reaction mixture was refluxed for 2 hrs and gave after work up andre-crystallization from ethanol 975 mg (22%) of 4,7-difluoro-1-indanone.

b) 4,7-Difluoroindene

This compound was prepared analogously to Examples 69a & 69b from4,7-difluoro-1-indanone (975 mg, 5.8 mmol) to give 475 mg (54%) of4,7-difluoroindene.

c) (±)-cis-Ethyl2,5-difluoro-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate

This compound was prepared analogously to Example 69c from4,7-difluoroindene (475 mg, 3.13 mmol). Purification on silica gelstarting with hexanes followed by hexanes with 2% diethyl ether andfinally hexanes with 5% diethyl ether afforded 205 mg of the cis-estercontaminated with 22% of the trans-ester.

d)(±)-cis-2,5-Difluoro-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid

This acid was synthesized analogously to Example 69d starting with 205mg cis-ester from Example 77c to give 120 mg of(±)-cis-2,5-difluoro-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylicacid containing a minor fraction of the corresponding trans-acid.

EXAMPLE 78N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-[5-(2-fluorophenoxy)-2-pyridinyl]urea

a) 5-(2-fluorophenoxy)-2-nitropyridine

Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) wasmixed with 3-5 ml of dry dimethylformamide and 2-fluorophenol (0.24 ml,2.7 mmol) was added to the stirred suspension. When the gas evolutionwas ceased the reaction mixture was heated at stirring at 60° C. and5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reactionmixture in one portion. The reaction mixture was stirred at 60° C. forabout 12 hours. The reaction mixture was then mixed with 50 ml of waterand extracted into methylene chloride (3×20 ml). Organic extract waswashed with water and brine, dried over magnesium sulfate andconcentrated by rotary evaporation. The resulting mixture was purifiedby column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 326mg (57% yield) of desired product.

¹H-NMR (CDCl₃): 8.34 (d, 1H), 8.25 (d, 1H), 7.36-7.40 (m, 1H), 7.23-7.34(m, 4H).

b) 5-(2-fluorophenoxy)-2-pyridinamine

5-(2-fluorophenoxy)-2-nitropyridine (326 mg) was mixed with 15-20 ml ofethanol and bubbled with argon. About 20 mg of Pd/C was added to thereaction mixture and hydrogen gas was applied at normal pressure andambient temperature for 3 h. The reaction was monitored by TLC. Afterthe reaction was complete, the reaction mixture was bubbled with argon,filtered through Celite and the solution obtained was concentrated byrotary evaporation to give 200 mg of desired aminopyridine (quantitativeyield).

¹H-NMR (CDCl₃): 790 (d, 1H), 7.10-7.20 (m, 2H), 7.00-7.05 (m, 2H),6.87-6.94 (m, 1H), 6.49 (d, 1H), 4.51 (br s, 2H).

c)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N-[5-(2-fluorophenoxy)-2-pyridinyl]urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ˜95% ee) was mixed with toluene (1,5 ml),triethylamine (1.1 eq), 5-(3-fluorophenyl)-2-aminopyridine (1.1 eq),DPPA (1.1 eq) and bubbled with argon for about 5 min. The reactionmixture was then heated at stirring at 110° C. for 3 h under in a closedvial. The reaction mixture was concentrated by rotary evaporation andpurified by column chromatography on silica (30 g, ethylacetate/hexane1:1). Desired product was obtained as white powder (61 mg, yield 64%).

¹H-NMR (CDCl₃): 9.44 (br s, 1H), 9.39 (br s, 1H), 7.53 (d, 1H),7.00-7.27 (m, 4H), 6.93-6.99 (m, 1H), 6.84 (d, 1H), 6.74 (m, 1H), 6.54(d tr, 1H), 4.43 (dd, 1H), 4.33 (dd, 1H), 3.79 (q, 1H), 2.57 (br tr,1H), 1.90-1.98 (m, 1H).

EXAMPLE 79N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-{5-[(4-fluorophenyl)(hydroxy)methyl]-2-pyridinyl}urea

a) (6-chloro-3-pyridinyl)(4-fluorophenyl)methanone

Aluminium chloride (2 g) was suspended in 3 ml of fluorobenzene. Asolution of 6-chloronicotinoyl chloride (1 g, 5.7 mmol) in 2 ml offluorobenzene was added to the stirred reaction mixture by syringe andstirred at 80° C. overnight in a closed vial. The reaction mixture wasdeluted with EtOAc and basified with aqueous sodium hydroxide (pH>8.5).The precipitate formed was removed by filtration. The organic solutionwas washed with water, dried over magnesium sulfate and concentrated byrotary evaporation. Desired product was purified by columnchromatography on silica (EtOAc/hexane) to give 1.22 g (90%).

¹H-NMR (CDCl₃): 8.75 (dd, 1H), 8.08 (dd, 1H), 7.82-7.87 (m, 2H), 7.50(dd, 1H), 7.21 (tr, 2H).

b) (6-amino-3-pyridinyl)(4-fluorophenyl)methanone

(6-Chloro-3-pyridinyl)(4-fluorophenyl)methanone (0.3 g) was mixed with 3ml of abs ethanol and 7 ml of liquid ammonia in an Ace ampule (suitablefor work under pressure). The ampule was closed with Teflon stopper(CAPFE O-ring) and heated at 145° C. for 14 h. The reaction mixture wascooled down and concentrated by rotary evaporation to give 0.22 g oforange-brown oil. The oil obtained was mixed with 1N HCl and precipitateformed was collected by filtration (starting material). The acidicsolution was washed with EtOAc and basified with 1N NaOH. Basic solutionwas extracted into EtOAc. Organic extract was washed with water andbrine, dried over magnesium sulfate. Purification by columnchromatography gave 60 mg of desired amine.

¹H-NMR (CDCl₃): 8.5 (d, ˜1H), 7.98 (dd, 1H), 7.79 (m, 2H), 7.15 (tr,2H), 6.55 (d, 1H), 4.95 (br s, 2H); LC-MS: M⁺217, M⁻215.

c)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-[5-(4-fluorobenzoyl)-2-pyridinyl]urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (40 mg, 0.18 mmol, ˜95% ee) was mixed with toluene (1 ml),triethylamine (1.1 eq), (6-amino-3-pyridinyl)(4-fluorophenyl)methanone(1.1 eq), DPPA (1.1 eq) and bubbled with argon. The reaction mixture wasthen heated at stirring at 110° C. for 3 h under in a closed vial. Thereaction mixture was concentrated by rotary evaporation and purified bycolumn chromatography on silica (30 g, ethylacetate/hexane 1:4). Thelast fraction collected contained desired product together with startingaminopyridine (25%, NMR data). The mixture was dissolved in methylenechloride and washed with 1N HCl, water and brine. Organic layer wasdried over magnesium sulphate. Concentration gave pure product as whitepowder (30 mg, yield 39%).

¹H-NMR (CDCl₃): 9.74 (br d, 1H), 9.57 (br s, 1H), 8.22 (d, 1H), 8.06(dd, 1H), 7.80 (m, 2H), 7.22 (t, 2H), 6.91 (d, 1H), 6.74-6.81 (m, 1H),6.57 (tr d, 1H), 4.49 (dd, 1H), 4.33 (dd, 1H), 3.86 (q, 1H), 2.65 (brtr, 1H), 1.97-2.03 (m, 1H). LC-MS: M⁺440, M⁻438.

d)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-{5-[(4-fluorophenyl)(hydroxy)methyl]-2-pyridinyl}urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-fluorobenzoyl)-2-pyridinyl]urea(20 mg) was dissolved in methanol and sodium borohydride (appr. 20 mg)was added to the reaction mixture in small portions. The reactionmixture was stirred for about 3 h at ambient temperature. The reactionwas monitored by TLC. The reaction mixture was diluted with water,acidified with 1N HCl and extracted into methylene chloride. Organicextract low as washed with water and bine, dried over magnesium sulfateand concentrated. Purification by column chromatography on silica(EtOAc/hexane) gave 12 mg of pure product.

¹H-NMR (CDCl₃): 9.60 (br s, 1H), 8.20 (br s, 1H), 7.72 (s, 1H), 7.47 (dtr, 1H), 7.27-7.32 (m, 2H), 7.04 (t, 2H), 6.75 (m, 1H), 6.52-6.62 (m,2H), 5.72 (br s, 1H), 4.43 (d tr, 1H), 4.32 (dd, 1H), 3.76 (q, 1H), 2.67(br s, 1H), 2.58 (br tr, 1H), 1.91-1.98 (m, 1H).

EXAMPLE 80N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-fluorobenzyl)-2-pyridinyl]urea

a) 5-(4-fluorobenzyl)-2-pyridinylamine

(6-Amino-3-pyridinyl)(4-fluorophenyl)methanone (30 mg, 0.138 mmol) wasdissolved in 1 ml of trifluoroacetic acid. 16 l of sulfuric acid (2.2eq) and 50 l of Et₃SiH and stirred at ambient temperature for 4 h in aclosed vial. The reaction mixture was poured into water, basified with2N sodium hydroxide and extracted into methylene chloride. Organicextract was washed with water and brine, concentrated and purified bycolumn chromatography on silica (10 g, EtOAc/hexane 1:1) to give 12 mgof desired product (43% yield).

b)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-fluorobenzyl)-2-pyridinyl]urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (11 mg, 0.05 mmol, ˜95% ee) was mixed with toluene (1 ml),triethylamine (1.1 eq), 5-(4-fluorobenzyl)-2-pyridinylamine (1.1 eq),DPPA (1.1 eq) and bubbled with argon. The reaction mixture was thenheated at stirring at 110° C. for 3 h under in a closed vial. Thereaction mixture was concentrated by rotary evaporation and purified bycolumn chromatography on silica (10 g, ethylacetate/hexane 1:1) to give4 mg (19%) of pure product.

¹H-NMR (CDCl₃): 9.60 (br s, 1H), 8.05 (br s, 1H), 7.59 (d, 1H), 7.29(dd, 1H), 7.05-7.10 (m, 2H), 6.99 (tr, 2H), 6.78 (m, 1H), 6.59 (m, 2H),4.45 (dd, 1H), 4.34 (dd, 1H) 3.74-3.86 (m, 3H), 2.59 (br tr, 1H),1.92-1.99 (m, 1H). LC-MS: M⁺426.

EXAMPLE 81N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-fluoro-4-(N-morpholinocarboxyamido)phenoxy)-2-pyridinyl]urea

a) 5-(3-fluoro-4-(N-morpholinocarboxyamido)phenoxy)-2-nitropyridine

Potassium tert-butoxide (452 mg, 4.03 mmol) was added to a solution of3-fluoro-4-(N-morpholinocarboxyamido)phenol (907 mg, 4.03 mmol) in DMF(6 ml) and the mixture was stirred for 1 hour at room temperature. Thenthe mixture was heated to 60° C. and 5-bromo-2-nitro pyridine (724 mg,3.57 mmol) was added and the mixture was stirred at 60° C. for 12 hours.Then the solvent was evaporated and the residue extracted between waterand methylene chloride. The organic phase was dried over sodium sulfateand evaporated. The resulting mixture was purified by columnchromatography on silica gel (0-½-1% EtOH/methylene chloride) to give743 mg (60% yield) of desired product.

¹H-NMR (CDCl₃): 8.39 (d, 1H), 8.30 (d, 1H), 7.53 (d, 1H), 7.53 (dd, 1H),6.98 (dd, 1H), 6.88 (dd, 1H), 3.81 (m, 4H), 3.68 (tr, 2H), 3.39 (tr,2H).

b) 5-(3-fluoro-4-(N-morpholinocarboxyamido)phenoxy)-2-pyridinamine

5-(3-fluoro-4-(N-morpholinocarboxyamido)phenoxy)-2-pyridinamine wassynthesized analogously to Example 2 from5-(3-fluoro-4-(N-morpholinocarboxyamido)phenoxy)-2-nitropyridine, after2 hours stirring under hydrogen. The crude product was purified bycolumn chromatography on silica gel (0-10% EtOH/methylene chloride) togive 411 mg of the title compound.

¹H-NMR (CDCl₃): 7.90 (d, 1H), 7.35 (dd, 1H), 7.20 (dd, 1H), 6.77 (dd,1H), 6.62 (dd, 1H), 6.54 (d, 1H), 4.49 (br, 2H), 3.81 (m, 4H), 3.65 (tr,2H), 3.37 (tr, 2H).

c)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-fluoro-4-(N-morpholinocarboxyamido)phenoxy)-2-pyridinyl]urea

The title compound was synthesized analogously to Example 3 from5-(3-fluoro-4-(N-morpholinocarboxyamido)phenoxy)-2-pyridinamine (47 mg,0.15 mmol), with the exception that the reaction mixture was worked upby extractions between EtAc and 5% citric acid followed by sat. aq.NaHCO₃, to give 34 mg of pure product as white powder (49% yield) aftersilica gel column chromatography (0-3½% EtOH/methylene chloride).

¹H-NMR (CDCl₃): 9.25 (br s, 1H), 7.66 (d, 1H), 7.44 (br s, 1H), 7.39(dd, 1H), 7.29 (dd, 1H), 6.81 (tr d, 1H), 6.77 (dd, 1H), 6.68 (d, 1H),6.63 (dd, 1H), 6.60 (d tr, 1H), 4.47 (dd, 1H), 4.32 (dd, 1H), 3.84-3.75(m, 5H), 3.66 (tr, 2H), 3.38 (tr, 2H), 2.62 (tr, 1H), 201-1.95 (m, 1H).LC-MS: M⁺541, M⁻539

EXAMPLE 82N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-fluoro-4-(N-morpholinomethyl)phenoxy)-2-pyridinyl]urea

a) 5-(3-fluoro-4-(N-morpholinomethyl)phenoxy)-2-nitropyridine

Borane in THF (1M, 0.79 ml, 0.79 mmol) was cooled to 0° C. Aconcentrated solution of5-(4-(N-morpholinocarboxyamido)-3-fluorophenoxy)-2-nitropyridine (363mg, 1.05 mmol) in THF was added through a syringe under argon. A fewminutes after complete addition, the cooling was removed and thereaction mixture was heated to 75° C. and stirred for 1½ hours. 6M HCl(0.15 ml) was added and the mixture was stirred until gas evolutionceased. The THF was evaporated and the residual aqueous solution wasbasified by addition of near saturated Na₂CO₃ solution. The resultingaqueous layer was extracted with methylene chloride, which was driedthrough sodium sulfate and evaporated. The title compound was isolatedfrom the residue by column chromatography on silica (0-6%EtOH/methylenechloride to give 73 mg (21% yield) as a yellow powder.

¹H-NMR (CDCl₃): 8.34 (d, 1H), 8.26 (d, 1H), 7.49 (tr, 1H), 7.46 (dd,1H), 6.88 (dd, 1H), 6.84 (dd, 1H), 3.73 (tr, 4H), 3.58 (s, 2H), 2.50(tr, 4H).

b) 5-(3-fluoro-4-(N-morpholinomethyl)phenoxy)-2-pyridinamine

A hot clear water solution (0.25 ml) of sodium sulphide nonahydrate (58mg, 0.24 mmol) and sulphur (14 mg, 0.447 mmol) was added to awater-dioxane mixture (1.12 ml, 1:1.5 v/v) of5-(3-fluoro-4-(N-morpholinomethyl)phenoxy)-2-nitropyridine (72 mg, 0.216mmol). The resulting solution was heated at 80° C. and stirred for 30min. Then the reaction was cooled and the volatile matter was evaporatedand the residue coevaporated with dioxane. The residue was slurried in30% MeOH-chloroform and the insoluble matter was filtered off and thefiltrate evaporated. The title compound was isolated from the resultingresidue by column chromatography on silica (1-4% EtOH/methylene chlorideto give 18 mg (28% yield) as a yellow powder.

¹H-NMR (CDCl₃): 7.91 (d, 1H), 7.26 (tr, 1H), 7.20 (dd, 1H), 6.68 (dd,1H), 6.60 (dd, 1H), 6.53 (dd, 1H), 4.40 (br s, 2H), 3.70 (tr, 4H), 3.51(s, 2H), 2.46 (tr, 4H).

c)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′[5-(3-fluoro-4-(N-morpholinomethyl)phenoxy)-2-pyridinyl]urea

The title compound was synthesized analogously to Example 3 from5-(3-fluoro-4-(N-morpholinomethyl)phenoxy)-2-pyridinamine (27 mg, 0.089mmol), with the exception that the reaction mixture was worked up byextractions between methylene chloride and 5% citric acid followed bysat. aq. NaHCO₃, to give 30 mg of product with >98% purity as whitepowder (72% yield) after silica gel column chromatography (0-4%EtOH/methylene chloride). ¹H-NMR (CDCl₃): 9.25 (br s, 1H), 7.61 (d, 1H),7.32 (tr, 1H), 7.26 (m, 2H), 6.81 (tr d, 1H), 6.70 (dd, 1H), 6.64-6.56(m, 3H), 4.47 (dd, 1H), 4.33 (dd, 1H), 3.79 (dd, 1H), 3.71 (tr, 4H),3.54 (s, 2H), 2.60 (tr, 1H), 2.48 (tr, 4H), 2.01-1.95 (m, 1H). LC-MS:M⁺527, M⁻525.

EXAMPLE 83N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-[5-(2-(N-morpholino)ethoxy)-2-pyridinyl]urea

a) 5-(2-(N-morpholino)ethoxy)-2-pyridinamine

Sodium (26 mg, 1.14 mmol) was dissolved in 2-(N-morpholino)ethanol (9.5ml). Then 2-amino-5-iodopyridine (500 mg, 2.27 mmol) was added followedby copper powder (202 mg, 3.18 mmol). The suspension was stirred at 160°C. for 40 hours. The solids were then filtered off and the volatilematter was evaporated. The residue was slurried in methylene chlorideand the insolubles were filtered off through Celite. The title compoundin the residual oil was isolated by column chromatography on silica(0-8% EtOH/methylene chloride. Yield 110 mg (21%).

¹H-NMR (CDCl₃): 7.80 (br s, 1H), 7.12 (dd, 1H), 6.48 (d, 1H), 4.25 (brs, 2H), 4.06 (tr, 2H), 3.74 (tr, 4H), 2.76 (tr, 2H), 2.56 (tr, 4H).

b)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-[5-(2-(N-morpholino)ethoxy)-2-pyridinyl]urea

The title compound was synthesized analogously to Example 3 from5-(2-N-morpholinoethoxy)-2-pyridinamine (33 mg, 0.15 mmol), with theexception that the reaction mixture was worked up by extractions betweenmethylene chloride and 5% citric acid followed by sat. aq. NaHCO₃, togive 12.6 mg of product with >95% purity as white powder (19% yield)after silica gel column chromatography (2-10% EtOH/methylene chloride).

¹H-NMR (CDCl₃): 9.45 (br s, 1H), 8.08 (s, 1H), 7.52 (d, 1H), 7.16 (dd,1H), 6.64-6.58 (m, 2H), 4.45 (dd, 1H), 4.33 (dd, 1H), 4.06 (tr, 2H),3.84 (q, 1H), 3.75 (m, 4H), 2.78 (tr, 2H), 2.61-2.54 (m, 5H), 2.01-1.95(m, 1H). LC-MS: M⁺447, M⁻445.

EXAMPLE 84N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-{5-[(6-bromo-3-pyridinyl)oxy]-2-pyridinyl}urea

a) 5-[(6-bromo-3-pyridinyl)oxy]-2-nitropyridine

5-[(6-bromo-3-pyridinyl)oxy]-2-nitropyridine was synthesized analogouslyto Example 1 from 5-bromo-2-nitropyridine (203 mg, 1 mmol) and2-bromo-3-hydroxypyridine (prepared according to WO9825920) to give 65mg of product (22%).

¹H-NMR (CDCl₃): 8.38 (d, 1H), 8.31-8.28 (m, 2H), 7.6 (dd, 1H), 7.49 (dd,1H), 7.35 (dd, (1H)

b) 5-[(6-bromo-3-pyrdinyl)oxy]-2-pyridinylamine

5-[(6-bromo-3-pyridinyl)oxy]-2-nitropyridine 65 mg, 0.22 mmol) wasdissolved in acetic acid (1.5 ml) and water (2 ml) and heated to 50degrees C. Iron powder (42 mg, 0.75 mmol) was added and the mixture wasleft for 1 h. Filtration and purification by column chromatography onsilica (ethyl acetate/hexane 2:1) gave 57 mg, 97% of desired product.

¹H-NMR (CDCl₃): 8.11 (d, 1H), 7.92 (d, 1H), 7.39 (d, 1H), 7.2 (dd, 1H),7.11 (dd, 1H), 6.54 (d, 1H).

c)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-{5-[(6-bromo-3-pyridinyl)oxy]-2-pyridiny}urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-{5-[(6-bromo-3-pyridinyl)oxy]-2-pyridinyl}ureawas synthesized analogously to Example 3 from5-[(6-bromo-3-pyridinyl)oxy]-2-pyridinylamine (37 mg, 0.14 mmol) and(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (32 mg, 0.14 mmol) to give 25 mg (36%) of pure product.

¹H-NMR (CDCl₃): 9.4 (br s, 2H), 8.12 (d, 1H), 7.63 (d, 1H), 7.43 (d,1H), 7.27 (dd, 1H), 7.12 (dd, 1H), 6.88 (d, 1H), 6.81 (m, 1H), 6.57 (m,1H), 4.49 (dd, 1H), 4.30 (dd, 1H), 4.83 (q, 1H), 2.62 (t, 1H), 1.98 (m,1H)

EXAMPLE 85N-[(1S,1aR,7bR)-4.7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-{5-[6-cyano-3-pyridinyl)oxy]-2-pyridinyl}urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-{5-[6-bromo-3-pyridinyl)oxy]-2-pyridinyl}urea(100 mg, 0.2 mmol), zink cyanide (70 mg, 0.6 mmol) andtertrakis(triphenylphospine)palladium(0) (46 mg, 20 mol % was dissolvedin DMF and heated at 85° C. for 24 h. under argon atmosphere. Thereaction mixture was then extracted between ethyl acetate and 1 Mpotassium carbonate. The organic solvent was removed under reducedpressure and the crude product was purified by chromatography (silica,1% methanol in diethyl ether) to give 25 mg (28%) of pure product.

¹H-NMR (CDCl₃+MeOD): 8.10 (d, 1H), 7.63 (d, 1H), 7.45 (d, 1H), 7.28 (dd,1H), 7.13 (dd, 1H), 6.85-6.79 (m, 2H), 6.64-6.58 (m, H), 4.46 (dd, 1H),4.32 (dd, 1H), 3.74 (q, 1H), 2.61 (t, 1H), 2.01-1.96 (m, 1H)

EXAMPLE 86N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-fluoroanilino)-2-pyridinyl]urea

a) N-(3-fluorophenyl)-6-nitro-3-pyridinamine

This compound was prepared from 2-nitro-5-bromopyridine and3-fluoroaniline using the catalytic amination procedure described forsimilar compounds in Tetrahedron Lett. Vol. 38, No 36, pp. 6359-63621997.

8.62 (d, 1H), 8.51 (dd, 1H), 8.11 (dd, 1H), 7.69 (dt, 1H), 7.41 (ddd,1H), 7.25 (dd, 1H), 6.61 (ddd, 1H), 6.39 (d, 1H).

b) N⁵-(3-fluorophenyl)-2,5-pyridinediamine

This compound was easily prepared fromN-(3-fluorophenyl)-6-nitro-3-pyridinamine 210 mg, 0.9 mmol) by catalytichydrogenation (Raney nickel at atmospheric pressure) in methanol to givethe desired product (180 mg, 98%)

c)N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(3-fluoroanilino)-2-pyridinyl]urea

N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl]-N′-[5-(3-fluoroanilino)-2-pyridinyl]ureawas synthesized analogously to Example 3 fromN⁵-(3-fluorophenyl)-2,5-pyridinediamine (180 mg, 0.88 mmol) and(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (200 mg, 0.88 mmol) to give 94 mg (25%).

¹H-NMR (CDCl₃): 9.2 (br s, 2H), 7.68 (d, 1H), 7.35 (dd, 1H), 7.2-7.15(m, 2H), 6.9-6.8 (m, 1H), 6.65-6.53 (m, 5H), 5.49 (s, 1H), 4.4 (dd, 2H),3.8 (q, 1H), 2.58 (t, 1H), 2.0-1,95 (m, 1H)

Biological Results

Extensive guidance on the assay of test compounds at the enzyme leveland in cell culture, including the isolation and/or selection of mutantHIV strains and mutant RT are found in DAIDS Virology Manual for HIVLaboratories complied by Division of AIDS, NIAID USA 1997. Resistancestudies, including rational for various drug escape mutants is describedin the HIV Resistance Collaborative Group Data Analysis Plan forResistance Studies, revised 31 Aug. 1999.

Compounds of the invention are assayed for HIV activity, for exampleusing multiple determinations with XTT in MTA-4 cells (Weislow et al, JNat Cancer Inst 1989, vol 81 no 8, 577 et seq), preferably includingdeterminations in the presence of 40-50% human serum to indicate thecontribution of protein binding. In short the XTT assay uses human Tcell line MT4 cells grown in RPMI 1640 medium supplemented with 10%fetal calf serum (or 40-50% human serum as appropriate), penicillin andstreptomycin seeded into 96 well microplates (2·10⁴ cells/well) infectedwith 10-20 TCID₅₀ per well of HIV-1_(IIIB) (wild type) or mutant virus,such as those bearing RT Ile 100, Cys 181 or Asn 103 mutations. Seriallydiluted test compounds are added to respective wells and the cultureincubated at 37° C. in a CO₂ enriched atmosphere and the viability ofcells is determined at day five or six with XTT vital dye. Results aretypically presented as ED₅₀ μM.

Compounds are preferably potent against wild type virus and mutant HIVvirus, especially virus comprising drug escape mutations. Drug escapemutations are those which arise in patients due to the selectivepressure of a prior art antiviral and which confer enhanced resistanceto that antiviral. The above cited Data Analysis Plan outlines relevantdrug escape mutants for each of the antiviral classes currently on themarket. Drug escape clones are readily isolated from HIV patients whoare failing on a particular antiviral therapy. Alternatively thepreparation of RT mutations on a known genetic background is shown inWO97/27319, WO99/61658 and WO00/73511 which also show the use of suchmutants in sensitivity profiling.

K103 N is a particularly relevant drug escape mutant in the context ofNNRTI therapy and compounds of the invention preferably have a low ED₅₀against this mutant, especially in assays mimicking the presence ofhuman serum. Compounds of the invention, such as those exemplified abovetypically show sub micromolar activities in such assays.

1. A compound of the formula Y:

where; R₁ is O, S; R₂ is pyrid-2-yl, substituted at the 5 position withthe —(CHR₁₁)_(p)-E-(CHR₁₁)_(q)—R₁₀ moiety; R₃ is H; R₄ and R₇ arefluoro; R₅ and R₆ are H; X is —(CR₈R₈′)_(n)-D-(CR₈R₈′)_(m)—; D is O; mis 1; n is 0; R₈ and R₈′ are H; E is —O; p and q are 0; R₁₀ ispyrid-3yl, optionally substituted with halo or cyano; andpharmaceutically acceptable salts and prodrugs thereof.
 2. A compoundaccording to claim 1, wherein R₁ is O.
 3. A compound according to claim1, wherein the cyclopropyl moiety has an enantiomeric excess of theconformation depicted in the partial formulae:

where X is as defined, Y is the bridge to the (substituted) phenyl ringdepicted in formula I and Z is bond to theurea-R₂—(CHR₁₁)_(p)-E-(CHR₁₁)_(q)—R₁₀ moiety depicted in formula I.
 4. Acompound according to claim 1 wherein the compound of formula Icomprises an enantiomeric excess of the isomer showing negative opticalactivity.
 5. A compound according to claim 1, wherein R₁₀ is cyano orfluoro substituted pyrid-3-yl.
 6. A pharmaceutical compositioncomprising a compound as defined in any one of claims 1, 3, 4, and 5,and a pharmaceutically acceptable vehicle or diluent therefor.
 7. Acomposition according to claim 6, further comprising 1 to 3 additionalHIV antivirals selected from the group consisting of AZT, ddI, ddC, D4T,3TC, DAPD, alovudine, abacavir, adefovir, adefovir dipivoxil,bis-POC-PMPA, foscarnet, efavirenz, trovirdine, capravirine, nevirapine,delaviridine, tipranavir, emtricitabine, omaciclovir, valomaciclovirstearate, TMC-126, TMC-125, TMC-120, efavirenz, loviride, ritonavir,kaletra, lopinavir, saguinavir, lasinavir, indinavir, amprenavir,amprenavir phosphate and nelfinavir.
 8. A method of treatment of HIV-1infections comprising administering to a patient infected with HIV-1 aneffective amount of the compound as defined by claim
 1. 9. The method ofclaim 8, wherein said HIV-1 infection is a drug escape mutant.
 10. Themethod of claim 9, wherein said drug escape mutant comprises the K1031mutation.
 11. The method of claim 8, wherein the compound has theformula:


12. A compound according to claim 5, wherein R₁₀ is 6-cyano-pyrid-3-yl.13. The compound of claim 1 with the formula:


14. A pharmaceutical composition comprising the compound of claim 12 anda pharmaceutically acceptable vehicle or diluent therefor.
 15. Thepharmaceutical composition of claim 13, further comprising 1-3additional antivirals selected from the group consisting of AZT, ddI,ddC, D4T, 3TC, DAPD, alovudine, abacavir, adefovir, adefovir dipivoxil,bis-POC-PMPA, foscarnet, efavirenz, trovirdine, capravirine, nevirapine,delaviridine, tipranavir, emtricitabine, omaciclovir, valomaciclovirstearate, TMC-126, TMC-125, TMC-120, efavirenz, loviride, ritonavir,kaletra, lopinavir, saquinavir, lasinavir, indinavir, amprenavir,amprenavir phosphate, and nelfinavir.